Brigatinib, an inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase (ALK), is an antineoplastic agent.1, 6, 7, 8, 9, 11
Brigatinib is used for the treatment of anaplastic lymphoma kinase ( ALK )-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.1, 2, 13, 14 Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC may be found at [Web].1 Brigatinib has been designated an orphan drug by the FDA for the treatment of ALK -positive, c-ros oncogene-1 ( ROS-1 )-positive, or epidermal growth factor receptor ( EGFR ) mutation-positive NSCLC.3 Guidelines for the treatment of stage IV NSCLC in patients with ALK driver alterations generally support the use of brigatinib as an option in the first-line setting and in the second-line setting following therapy with crizotinib.35
A relatively small subset of patients with NSCLC (approximately 3-7%) have ALK -positive disease, which indicates potential responsiveness to ALK inhibitor therapy (e.g., alectinib, brigatinib, ceritinib, crizotinib).6, 8, 9, 10 Patients with this form of lung cancer typically are nonsmokers or have a history of light smoking, are female, and are younger in age and often have adenocarcinoma histology.8, 9, 10, 11 Although crizotinib is highly active in patients with ALK -positive NSCLC, most patients treated with the drug eventually experience disease progression, limiting the drug's long-term therapeutic potential.6, 8, 9, 11 Disease progression in patients receiving crizotinib can result from acquired resistance mutations in ALK , amplification of gene expression, activation of alternate signaling pathways, and/or progression of brain metastases (because of poor distribution of crizotinib into the CSF).6, 7, 8, 9, 11
Efficacy and safety of brigatinib for the treatment of advanced ALK -positive NSCLC in patients naive to ALK inhibitor therapy were demonstrated in a randomized, open-label, multicenter trial (ALTA 1L).1, 13, 14 Patients enrolled in the study had received up to 1 prior chemotherapy regimen in the locally advanced or metastatic setting.1 Neurologically stable patients with treated or untreated CNS metastases, including leptomeningeal metastases, were eligible.1 Patients with a history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis were excluded from the study.1 The primary efficacy end point was progression-free survival as assessed by a blinded independent review committee.1
In this study, 275 patients were randomized to receive brigatinib 180 mg once daily (following an initial dosage of 90 mg once daily for 7 days) or crizotinib 250 mg orally twice daily.1 The median age of patients enrolled in this study was 59 years (range: 27-89); 59% of patients were white, 39% were Asian, 55% were female, 58% were never smokers, 39% had an ECOG performance status of 0, and 56% had an ECOG performance status of 1.1 Most (93%) of the patients had stage IV disease, 27% had received prior chemotherapy for locally advanced or metastatic disease, 14% had received prior CNS radiation, 31% had bone metastases, and 20% had liver metastases.1 The median duration of therapy was 9.2 months (range: 0.1-18.4) in the brigatinib treatment group and 7.4 months (range: 0.1-19.2 months) in the crizotinib treatment group.13
At the time of the interim analysis (median follow-up of 11 months), median progression-free survival was substantially prolonged in brigatinib-treated patients compared with crizotinib-treated patients (24 versus 11 months).1 Overall response rate, intracranial overall response rate, and intracranial confirmed response were also substantially improved in patients receiving brigatinib compared with those receiving crizotinib.1 Progression-free survival at the time of final analysis (at a median follow-up of 40.4 months) remained similar to the interim results.14
Efficacy and safety of brigatinib for the treatment of NSCLC previously treated with crizotinib are based principally on the results of a multicenter, two-arm, open-label, phase 2 study (ALTA) that enrolled a total of 222 adults with locally advanced or metastatic ALK -positive NSCLC who had experienced disease progression while receiving crizotinib therapy.1, 2 ALK rearrangement was required for study entry and was confirmed by an FDA-approved diagnostic test or a different test with adequate archival tissue to confirm ALK rearrangement by the Vysis® ALK Break Apart fluorescence in situ hybridization (FISH) Probe Kit test.1, 2 Patients were randomized in a 1:1 ratio to initially receive brigatinib in a dosage of 90 mg once daily (arm A) or 180 mg once daily (following an initial dosage of 90 mg once daily for 7 days) (arm B) until disease progression, unacceptable toxicity, or consent withdrawal occurred.1, 2 Patients in arm A could receive brigatinib 180 mg once daily after objective progression occurred on a dosage of 90 mg once daily.2 The primary efficacy end point was confirmed overall response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as evaluated by a central independent review committee (IRC); additional outcome measures included investigator-assessed overall response rate, duration of response, overall response rate in patients with CNS metastases, and duration of response in patients with CNS metastases.1 The median age of patients enrolled in the study was 54 years (range: 18-82 years); 67% of enrolled patients were white and 31% were Asian; and 57% were female.1, 2 Stage IV disease was present in 98% of the patients and 97% had adenocarcinoma histology, 74% of the patients had received prior systemic chemotherapy, and 64% of patients had an objective response to prior crizotinib treatment.1 CNS metastases were present in 69% of patients and 61% had previously received radiation to the brain.1
The median duration of follow-up in the ALTA study was 8 months (range: 0.1-20.2 months).1 The IRC-assessed overall response rate in patients receiving brigatinib 180 mg daily was 53%; partial responses were achieved in 48% of patients and 4.5% had a complete response.1, 2 The investigator-assessed overall response rate in patients receiving brigatinib 180 mg daily was 54%; partial responses were achieved in 50% of patients and 3.6% had a complete response.1, 2 Patients receiving brigatinib 90 mg daily had IRC- or investigator-assessed overall response rates of 48 or 45%, respectively; IRC- or investigator-assessed partial responses were achieved in 45 or 44% of patients, respectively, and complete responses were achieved in 3.6 or 0.9% of patients, respectively.1, 2 The median IRC-assessed duration of response was 13.8 months in both dosage groups and the median investigator-assessed duration of response was 13.8 months in the 90-mg dosage group and 11.1 months in the 180-mg dosage group.1
In the subgroup of 44 patients with measurable brain metastases at baseline in the ALTA study, the IRC-assessed intracranial overall response rate was 67% (all partial responses) in patients receiving brigatinib 180 mg daily and 42% (7.7% complete responses and 35% partial responses) in patients receiving brigatinib 90 mg daily.1, 2 The median duration of intracranial response was 5.6 months in the 180-mg dosage group and could not be estimated at the time of analysis in the 90-mg dosage group.1, 2 Among the 23 patients who demonstrated an intracranial response to brigatinib therapy, 78% of the patients receiving 90 mg once daily and 68% of the patients receiving 180 mg once daily maintained a response for at least 4 months.1
First-line Therapy for Metastatic Non-small Cell Lung Cancer
The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations such as ALK mutations.35 ASCO/OH state that alectinib or brigatinib should be offered in the first-line setting in patients with stage IV NSCLC and driver alterations in ALK .35 ASCO/OH also state that if alectinib or brigatinib are not available, ceritinib or crizotinib should be offered in the first-line setting.35
Previously Treated Metastatic Non-small Cell Lung Cancer
In the second-line setting, ASCO/OH state that alectinib, brigatinib, or ceritinib should be offered in patients who received initial therapy with crizotinib.35
Brigatinib is administered orally once daily without regard to food.1 Swallow brigatinib tablets whole and do not crush or chew.1
If a dose of brigatinib is missed or vomiting occurs after taking a dose, the prescribed dose should be taken at the next scheduled time; an additional dose should not be administered to replace the missed dose.1
Store brigatinib tablets at 20-25°C (excursions permitted between 15-30°C).1
The recommended adult dosage of brigatinib for the treatment of anaplastic lymphoma kinase ( ALK )-positive metastatic non-small cell lung cancer (NSCLC) is 90 mg once daily for the first 7 days, followed by an increase to 180 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
Following treatment interruptions of 14 or more days for reasons other than adverse reactions, resume brigatinib at a dosage of 90 mg once daily for 7 days, then increase to the previously tolerated dosage.1
Dosage Modification for Toxicity
Dosing interruption and/or dosage reduction of brigatinib may be necessary based on individual safety and tolerability.1
In the ALTA study, dosage reduction because of adverse effects was necessary in 7.3 or 20% of patients receiving brigatinib 90 mg daily or 180 mg daily, respectively (most commonly because of elevated serum CK concentrations).1, 2 In the ALTA 1L trial, dosage reduction because of any adverse event occurred in 29% of patients treated with brigatinib 180 mg once daily.13
If dosage reduction is necessary in a patient receiving 90 mg of brigatinib once daily, the dosage should be reduced to 60 mg once daily.1 If further dosage reduction is necessary, the drug should be permanently discontinued.1
If dosage reduction is necessary in a patient receiving 180 mg of brigatinib once daily, an initial dosage reduction to 120 mg once daily is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 90 mg once daily.1 If dosage reduction from 90 mg once daily is necessary, a dosage of 60 mg once daily is recommended.1 If a dosage of 60 mg once daily is not tolerated, brigatinib should be permanently discontinued.1
Once the dosage of brigatinib has been reduced because of adverse reactions, the dosage should not be subsequently increased.1
Interstitial Lung Disease/Pneumonitis
If new grade 1 pulmonary symptoms occur during the first 7 days of treatment, withhold brigatinib therapy until recovery to baseline.1 Therapy may then be resumed at the same dosa dosage should not be increased to 180 mg once daily if interstitial lung disease (ILD)/pneumonitis is suspected.1
If new grade 1 pulmonary symptoms occur after the first 7 days of treatment, withhold brigatinib therapy until recovery to baseline.1 Therapy may then be resumed at the same dosage.1
If new grade 2 pulmonary symptoms occur during the first 7 days of treatment, withhold brigatinib therapy until recovery to baseline.1 Therapy may then be resumed at the next lower dosa dosage should not be increased if ILD/pneumonitis is suspected.1
If new grade 2 pulmonary symptoms occur after the first 7 days of treatment, withhold brigatinib therapy until recovery to baseline.1 If ILD/pneumonitis is suspected, therapy may be resumed at the next lower dosa otherwise, therapy may be resumed at the same dosage.1
If grade 1 or 2 ILD/pneumonitis recurs , permanently discontinue brigatinib therapy.1
If grade 3 or 4 ILD/pneumonitis occurs, permanently discontinue brigatinib therapy.1
If grade 3 hypertension (i.e., systolic blood pressure of 160 mm Hg or greater or diastolic blood pressure of 100 mm Hg or greater requiring medical intervention and more than one antihypertensive agent or more intensive therapy than previously used) occurs, withhold brigatinib therapy until recovery to grade 1 or less hypertension (i.e., systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg).1 Therapy may then be resumed at the next lower dosage.1
If grade 3 hypertension recurs , withhold brigatinib therapy until recovery to grade 1 or less; resume therapy at the next lower dosage or permanently discontinue brigatinib.1
If grade 4 hypertension (i.e., life-threatening consequences, requiring urgent intervention) occurs, withhold brigatinib therapy until recovery to grade 1 or less; therapy may then be resumed at the next lower dosage or permanently discontinue brigatinib.1
If grade 4 hypertension recurs , permanently discontinue brigatinib.1
If symptomatic, but non-life-threatening, bradycardia occurs, withhold brigatinib therapy until recovery to asymptomatic bradycardia or to a resting heart rate of at least 60 beats/minute.1 If concomitant drugs known to cause bradycardia are identified and discontinued or their dosage is adjusted, brigatinib therapy may be resumed at the same dosage upon recovery to asymptomatic bradycardia or to a resting heart rate of at least 60 beats/minute.1 If no concomitant drugs known to cause bradycardia are identified or if discontinuance or dosage adjustment of such concomitant drugs is not possible, resume brigatinib at the next lower dosage upon recovery to asymptomatic bradycardia or to a resting heart rate of at least 60 beats/minute.1
If life-threatening bradycardia requiring urgent intervention occurs in patients receiving concomitant contributory drugs, withhold brigatinib therapy until recovery to asymptomatic bradycardia or to a resting heart rate of at least 60 beats/minute.1 If such concomitant drugs are discontinued or the dosage adjusted, brigatinib therapy may be resumed at the next lower dosage with frequent monitoring as clinically indicated.1 Brigatinib should be permanently discontinued in case of recurrence.1
If life-threatening bradycardia requiring urgent intervention occurs in patients not receiving concomitant contributory drugs, permanently discontinue brigatinib.1
If grade 2 or 3 visual disturbance occurs, withhold brigatinib therapy until recovery to grade 1 or baseline.1 Therapy may then be resumed at the next lower dosage.1
If grade 4 visual disturbance occurs, permanently discontinue brigatinib.1
If an elevation in serum CK concentrations exceeding 5 times the upper limit of normal (ULN; i.e., grade 3 or 4) occurs concomitantly with grade 2 or higher muscle pain or weakness, withhold brigatinib therapy until CK concentrations return to baseline values or decrease to no more than 2.5 times the ULN (i.e., grade 1 or less).1 Brigatinib may then be resumed at the same dosage.1 If an elevation in serum CK concentrations exceeding 5 times the ULN recurs , withhold brigatinib until CK concentrations return to baseline values or decrease to grade 1 or less; brigatinib therapy may then be resumed at the next lower dosage.1
If an elevation in serum amylase or lipase concentrations exceeding 2 times the ULN (i.e., grade 3) occurs, withhold brigatinib therapy until amylase or lipase concentrations return to baseline values or decrease to no more than 1.5 times the ULN (i.e., grade 1 or less).1 Brigatinib may then be resumed at the same dosage.1 If grade 3 elevation in serum amylase or lipase concentrations recurs , withhold brigatinib until amylase or lipase concentrations return to baseline values or decrease to grade 1 or less; brigatinib therapy may then be resumed at the next lower dosage.1
If an elevation in serum amylase or lipase concentrations exceeding 5 times the ULN (i.e., grade 4) occurs, withhold brigatinib therapy until amylase or lipase concentrations return to baseline values or decrease to grade 1 or less.1 Brigatinib therapy may then be resumed at the next lower dosage.1
If a grade 3 or 4 elevation (>5 times the ULN) of either AST or ALT with bilirubin ≤2 times the ULN occurs, withhold brigatinib therapy until recovery to grade 1 or less (≤3 times the ULN) or to baseline.1 Brigatinib may then be resumed at the next lower dose.1
If grade 2 to 4 elevation (>3 times the ULN) of ALT or AST with concurrent total bilirubin elevation >2 times the ULN in the absence of cholestasis or hemolysis occurs, brigatinib therapy should be permanently discontinued.1
If hyperglycemia with serum glucose concentrations exceeding 250 mg/dL (i.e., grade 3) occurs and adequate hyperglycemic control cannot be achieved despite optimal antidiabetic agent therapy, withhold brigatinib until adequate control of hyperglycemia is achieved; brigatinib may then be resumed at the next lower dosage or discontinued permanently.1
If any other grade 3 adverse reaction occurs, withhold brigatinib therapy until recovery to baseline.1 Brigatinib therapy may then be resumed at the same dosage.1 If the grade 3 adverse reaction recurs , brigatinib therapy should be withheld until recovery to baseline; brigatinib may then be resumed at the next lower dosage or the drug discontinued.1
If any other grade 4 adverse reaction occurs, withhold brigatinib therapy until recovery to baseline.1 Brigatinib therapy may then be resumed at the next lower dosage or permanently discontinued.1 If the grade 4 adverse reaction recurs , brigatinib therapy should be permanently discontinued.1
Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
Avoid concomitant use of brigatinib with drugs that are potent or moderate inhibitors of cytochrome P-450 (CYP) isoenzyme 3A.1
If concomitant use of brigatinib with a potent CYP3A inhibitor cannot be avoided, reduce the once daily dosage of brigatinib by approximately 50% (e.g., from 180 mg to 90 mg once daily; from 90 mg to 60 mg once daily).1
If concomitant use of brigatinib with a moderate CYP3A inhibitor cannot be avoided, reduce the dosage of brigatinib by approximately 40% (e.g., from 180 mg to 120 mg once daily; from 120 mg to 90 mg once daily; from 90 mg to 60 mg once daily).1
If concomitant use of the potent or moderate CYP3A inhibitor is discontinued, resume brigatinib dosage that was tolerated prior to initiation of the CYP3A inhibitor.1
Avoid concomitant use of brigatinib with drugs that are potent or moderate inducers of CYP3A.1
If concomitant use of brigatinib with a moderate CYP3A inducer cannot be avoided, increase the dosage of brigatinib in 30-mg increments (as tolerated) after 7 days of therapy, up to a maximum of twice the brigatinib dose that was tolerated prior to initiation of the moderate CYP3A inducer.1 If concomitant use of the moderate CYP3A inducer is discontinued, resume the brigatinib dose that was tolerated prior to initiation of the moderate CYP3A inducer.1
In patients with severe hepatic impairment (Child-Pugh class C), reduce the dosage of brigatinib by approximately 40% (e.g., from 180 mg to 120 mg once daily; from 120 mg to 90 mg once daily; from 90 mg to 60 mg once daily).1
No dosage adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1
In patients with severe renal impairment (creatinine clearance 15-29 mL/minute), reduce the dosage of brigatinib by approximately 50% (e.g., from 180 mg to 90 mg once daily; from 90 mg to 60 mg once daily).1
No dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Interstitial Lung Disease/Pneumonitis
Severe, life-threatening, or fatal adverse pulmonary reactions consistent with interstitial lung disease (ILD)/pneumonitis may occur in patients receiving brigatinib.1, 2 In the ALTA study, ILD or pneumonitis occurred in 3.7% of patients receiving brigatinib 90 mg once daily and in 9.1% of patients receiving the recommended dosage regimen (180 mg once daily with a 7-day lead-in at 90 mg once daily), and grade 3 or 4 adverse reactions consistent with possible ILD or pneumonitis occurred in 2.7% of patients receiving the drug.1, 2 Adverse pulmonary symptoms consistent with possible ILD/pneumonitis occurred early (i.e., within 9 days of initiation of therapy; median onset was 2 days) in 6.4% of patients in this study,1 and all patients were receiving brigatinib 90 mg once daily at the time of symptom onset.2 In the ALTA 1L trial, ILD or pneumonitis occurred in 5.1% of patients receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily).1 These events occurred within 8 days of initiation of brigatinib therapy in 2.9% of patients and grade 3 or 4 adverse reactions occurred in 2.2% of patients.1
Monitor patients receiving brigatinib for new or worsening respiratory symptoms (e.g., dyspnea, cough), particularly during the first week of initiating therapy.1, 2 If such respiratory manifestations occur, interrupt brigatinib therapy and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, pneumonia).1, 2 If ILD/pneumonitis is confirmed or ILD/pneumonitis recurs, dosage reduction or discontinuance of therapy may be necessary depending on the severity.1
Brigatinib may cause hypertension.1 In the ALTA study, hypertension occurred in 21% of patients; grade 3 or 4 hypertension occurred in 5.9% of patients receiving the recommended dosage regimen of brigatinib (180 mg once daily with a 7-day lead-in at 90 mg once daily).1 Among patients receiving brigatinib 90 mg once daily in the ALTA study, hypertension occurred in 11% of patients.1 In the ALTA 1L trial, hypertension occurred in 32% of patients receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily); grade 3 hypertension occurred in 13% of patients.1
Blood pressure should be controlled prior to initiating therapy with brigatinib.1 Blood pressure should be monitored 2 weeks after treatment initiation and at least monthly during therapy with the drug.1 If severe hypertension (i.e., grade 3) occurs despite optimal antihypertensive therapy, interrupt brigatinib therapy until blood pressure is controlled.1 Upon resolution or improvement of hypertension to grade 1, resume brigatinib at the same dosage.1 Consider permanent discontinuance of brigatinib therapy if grade 4 hypertension occurs or if grade 3 hypertension recurs.1
Brigatinib may cause bradycardia.1 In the ALTA study, bradycardia with a heart rate of less than 50 beats/minute was reported in 7.6 or 5.7% of patients receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily) or 90 mg once daily, respectively.1 Grade 2 bradycardia occurred in one patient (0.9%) receiving the 90-mg daily dosage.1 In the ALTA 1L trial, bradycardia occurred in 8.1% of patients treated with brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily); grade 3 bradycardia occurred in 1 patient (0.7%).1
Monitor heart rate and blood pressure periodically during brigatinib therapy.1 Monitor patients more frequently if concomitant use with a drug known to cause bradycardia cannot be avoided.1 If symptomatic or life-threatening bradycardia occurs, withhold brigatinib therapy.1 Evaluate concomitant therapy to identify any drugs that may cause bradycardia; adjust dosage or discontinue such drugs, and then resume brigatinib at the same dosage following resolution of symptomatic bradycardia.1 If no concomitant therapy with a drug known to cause bradycardia is identified, reduce the dosage of brigatinib following resolution of symptomatic bradycardia.1 Discontinue brigatinib if life-threatening bradycardia occurs in the absence of contributing concomitant medications.1
In the ALTA study, adverse reactions leading to visual disturbances, including blurred vision, diplopia, and reduced visual acuity, were reported in 10 or 7.3% of patients receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily) or 90 mg once daily, respectively.1 Grade 3 macular edema and cataract each occurred in one patient receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily).1 In the ALTA 1L trial, grade 1 or 2 adverse reactions resulting in visual disturbance were reported in 7.4% of patients receiving brigatinib.1
In patients who report new or worsening visual symptoms of grade 2 or higher severity, interrupt brigatinib therapy and perform an ophthalmologic evaluation.1 Dosage reduction or drug discontinuance may be required depending on the severity.1
In the ALTA study, elevated serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations were reported in 48% and were grade 3 or 4 in 12% of patients receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily).1 Among patients receiving brigatinib 90 mg once daily, elevated serum CK concentrations were reported in 27% of patients; 2.8% of these patients had grade 3 or 4 elevations in CK concentrations.1 Dosage modification because of elevated serum CK concentrations was required in 4.5 or 1.8% of patients receiving brigatinib 180 or 90 mg daily, respectively.1 In the ALTA 1L trial, elevated serum CK concentrations were reported in 81% of patients treated with brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily); grade 3 or 4 elevations occurred in 24% of patients.1 In the ALTA 1L trial, dosage modification because of elevated serum CK concentrations was required in 15% of patients.1
Monitor serum CK concentrations periodically during brigatinib therapy.1 Temporary interruption followed by resumption of therapy at the same or at a reduced dosage of brigatinib may be necessary, depending on the severity of the CK elevation.1
In the ALTA study, elevated serum amylase concentrations and grade 3 or 4 elevated serum amylase concentrations were reported in 39 and 2.7% of patients receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily), respectively.1 Elevated serum lipase concentrations and grade 3 or 4 elevated serum lipase concentrations were reported in 45 and 5.5% of patients receiving the 180-mg daily dosage, respectively.1 Among patients receiving brigatinib 90 mg once daily, elevated serum amylase concentrations and grade 3 or 4 elevated serum amylase concentrations were reported in 27 and 3.7% of patients, respectively.1 Elevated serum lipase concentrations and grade 3 or 4 elevated serum lipase concentrations were reported in 21 and 4.6% of patients receiving the 90-mg daily dosage of brigatinib, respectively.1 In the ALTA 1L trial, elevated serum amylase or lipase concentrations were reported in 52 or 59%, respectively, of patients treated with brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily); grade 3 or 4 elevations of serum amylase or lipase concentrations occurred in 6.8 or 17% of patients, respectively.1
Serum amylase and lipase concentrations should be monitored periodically during brigatinib therapy.1 Temporary interruption followed by resumption of therapy at the same or a reduced dosage of brigatinib may be necessary, depending on the severity of the amylase and/or lipase elevation.1
Hepatotoxicity may occur in patients receiving brigatinib.1 In the ALTA study, elevated AST concentrations and grade 3 or 4 AST elevations were reported in 38% and 0.9% of patients in the brigatinib 90 mg once daily group.1 Elevations in ALT concentrations and grade 3 or 4 ALT elevations occurred in 34% and 0 patients in the brigatinib 90 mg once daily group.1 In the brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily) group, AST elevations occurred in 65% of patients, ALT elevations in 40%, grade 3 or 4 AST elevations in 0 patients, and grade 3 or 4 ALT elevations in 2.7% of patients.1
In the ALTA 1L trial, AST elevations and grade 3 or 4 AST elevations occurred in 72% and 4.5% of patients, respectively.1 ALT elevations were reported in 52% of patients and grade 3 or 4 ALT elevations in 5.2% of patients.1 One patient (0.7%) experienced serious hepatocellular injury.1
Monitor AST, ALT, and total bilirubin during treatment with brigatinib, especially during the initial 3 months.1 Withhold brigatinib for grade 3 or 4 hepatic enzyme elevation with bilirubin ≤2 times the ULN.1 Upon resolution or recovery to grade 1 or less (≤3 times the ULN) or to baseline, resume brigatinib at a next lower dose.1 Permanently discontinue brigatinib for grade 2 or 4 hepatic enzyme elevation with concurrent total bilirubin elevations >2 times the ULN in the absence of cholestasis or hemolysis.1
Hyperglycemia may occur in patients receiving brigatinib.1 In the ALTA study, new or worsening hyperglycemia occurred in 43% of brigatinib-treated patients; grade 3 hyperglycemia (based on fasting serum glucose concentrations) occurred in 3.7% of patients receiving the drug.1 Among patients with diabetes mellitus or glucose intolerance at baseline, 10% required initiation of insulin during brigatinib therapy.1 In the ALTA 1L trial, new or worsening hyperglycemia occurred in 56% of patients receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily); grade 3 hyperglycemia occurred in 7.5% of patients.1
Assess fasting serum glucose concentrations prior to initiation of brigatinib and monitor periodically during treatment.1 Antidiabetic agents should be initiated or optimized as necessary.1 If adequate glycemic control cannot be achieved despite optimal medical management, interrupt brigatinib therapy until hyperglycemia is adequately controlled.1 Dosage reduction or discontinuance of therapy may be necessary depending on the severity of hyperglycemia.1
Photosensitivity may occur in patients receiving brigatinib.1 In the ALTA study, photosensitivity occurred in 0.9% of patients receiving brigatinib 90 mg daily; however, grade 3 to 4 photosensitivity was not reported in patients receiving brigatinib 90 mg daily or 180 mg once daily (with a 7-day lead-in at 90 mg once daily).1 In the ALTA 1L trial, photosensitivity occurred in 3.7% of patients receiving brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily); grade 3 or 4 photosensitivity occurred in 0.7% of patients.1
Advise patients to limit sun exposure during brigatinib therapy, and for at least 5 days after discontinuation of treatment.1 Counsel patients to wear a hat and protective clothing when outdoors, and to use a broad-spectrum sunscreen and lip balm (SPF ≥30) for protection against sunburn.1
Fetal/Neonatal Morbidity and Mortality
Brigatinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 There are no clinical data on the use of brigatinib in pregnant women.1 Dose-related skeletal abnormalities were observed when the drug was administered to pregnant animals during the period of organogenesis at dosages equivalent to approximately 0.7 times the human exposure achieved with the recommended dosage.1 In addition, increased post-implantation loss, malformations, and decreased fetal body weight were observed in animals at dosages equivalent to approximately 1.26 times the human exposure achieved at the recommended dosage.1
Avoid pregnancy during brigatinib therapy.1 Females of reproductive potential should use effective nonhormonal contraception during brigatinib therapy and for at least 4 months after the drug is discontinued.1 In addition, men with female partners of reproductive potential should use effective methods of contraception while receiving brigatinib therapy and for at least 3 months after the drug is discontinued.1 If brigatinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Although there are no clinical data in pregnant women to date, animal studies and its mechanism of action suggest that brigatinib may cause fetal harm.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating brigatinib therapy.1 Advise females of reproductive potential to use effective contraception during therapy and for at least 4 months after the final dose.1 Advise males with female partners of reproductive potential to use effective contraception during brigatinib therapy and for at least 3 months after the final dose.1
Based on findings from animal studies, brigatinib may reduce fertility in males.1
It is not known whether brigatinib is distributed into human milk or if the drug has any effect on milk production or the breast-fed infant.1 Because of the potential for adverse reactions to brigatinib in breast-fed infants, advise females not to breast-feed while receiving the drug and for at least 1 week after the drug is discontinued.1
Safety and efficacy of brigatinib have not been established in pediatric patients.1
Clinical studies of brigatinib did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1 In the principal efficacy studies evaluating brigatinib in patients with NSCLC, 26.7% were ≥65 years of age and 7.5% were ≥75 years of age.1 No clinically important differences in safety or efficacy were observed between geriatric patients and younger adults in this study.1
Age does not have a clinically important effect on the pharmacokinetics of brigatinib.1
In a population pharmacokinetic analysis, mild hepatic impairment (total bilirubin concentrations not exceeding the upper limit of normal [ULN] with AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding 1 but not exceeding 1.5 times the ULN with any AST concentration) did not affect systemic exposure to brigatinib.1
Following a single dose of brigatinib 90 mg, unbound systemic exposure of brigatinib was 37% higher in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function.1 In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), systemic exposure of the drug was similar to that in patients with normal hepatic function.1
In a population pharmacokinetic analysis, mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute) did not affect systemic exposure to brigatinib.1
Following administration of a single 90-mg dose of brigatinib, AUC of brigatinib was 86% higher in individuals with severe renal impairment (creatinine clearance 15-29 mL/minute) compared with individuals with normal renal function.1
The most common adverse reactions (reported in at least 25% of patients) include diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.1
Brigatinib is metabolized principally by cytochrome P-450 (CYP) isoenzymes 2C8 and 3A4.1 In vitro studies indicate that brigatinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate of organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion transporter (MATE) 1, MATE2K, or bile salt export pump (BSEP).1
In vitro studies indicate that brigatinib inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K.1 Brigatinib does not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or BSEP.1
Brigatinib induces CYP3A and also may induce CYP2C isoenzymes via activation of the pregnane X receptor (PXR).1 Brigatinib and its principal metabolite do not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 at clinically relevant concentrations.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of brigatinib with potent or moderate inhibitors of CYP3A may increase plasma concentrations of brigatinib, which may result in increased adverse effects.1 Concurrent administration of the potent CYP3A inhibitor itraconazole (200 mg twice daily) and brigatinib (single 90-mg dose) increased peak plasma concentrations and AUC of brigatinib by 21 and 101%, respectively, compared with administration of brigatinib alone.1 Concomitant use of brigatinib with a moderate CYP3A inhibitor is expected to increase the AUC of brigatinib by approximately 40%.1
The manufacturer states that concomitant use of potent or moderate CYP3A inhibitors, including grapefruit products, should be avoided during brigatinib therapy.1 If concomitant use of a potent CYP3A inhibitor cannot be avoided, reduce the once daily dosage of brigatinib by approximately 50% (e.g., from 180 mg to 90 mg once daily; from 90 mg to 60 mg once daily).1 If concomitant use of brigatinib with a moderate CYP3A inhibitor cannot be avoided, reduce the dosage of brigatinib by approximately 40% (e.g., from 180 mg to 120 mg once daily; from 120 mg to 90 mg once daily; from 90 mg to 60 mg once daily).1 If concomitant use of the potent or moderate CYP3A inhibitor is discontinued, the brigatinib dosage should be returned to the dosage that was tolerated prior to initiation of the potent CYP3A inhibitor.1
Concomitant administration of the potent CYP2C8 inhibitor gemfibrozil (600 mg twice daily) and brigatinib (single 90-mg dose) decreased peak plasma concentrations and the AUC of brigatinib by 41 and 12%, respectively.1 The manufacturer states that the effect of gemfibrozil on the pharmacokinetics of brigatinib is not considered clinically important and that the underlying mechanism for the decreased exposure of brigatinib is not known.1
Concomitant use of brigatinib with potent or moderate inducers of CYP3A (e.g., carbamazepine, phenytoin, rifampin) may decrease plasma concentrations and reduce efficacy of brigatinib and should be avoided.1 When the potent CYP3A inducer rifampin (600 mg daily) was administered concomitantly with brigatinib (single 180-mg dose), peak plasma concentrations and AUC of brigatinib decreased by 60 and 80%, respectively.1
Avoid concomitant use of brigatinib with potent or moderate CYP3A inducers.1 If concomitant use of brigatinib with a moderate CYP3A inducer cannot be avoided, increase the dosage of brigatinib in 30-mg increments (as tolerated) after 7 days of therapy, up to a maximum of twice the brigatinib dose that was tolerated prior to initiation of the moderate CYP3A inducer.1 If concomitant use of the moderate CYP3A inducer is discontinued, resume the brigatinib dose that was tolerated prior to initiation of the moderate CYP3A inducer.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Brigatinib induces CYP3A in vitro; therefore, concomitant use of brigatinib and drugs metabolized by CYP3A may result in decreased concentrations and loss of efficacy of the CYP3A substrate.1
Substrates of Drug Transport Systems
Brigatinib inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro and potentially may increase concentrations of drugs that are substrates of these transport systems.1
Drugs Associated with Bradycardia
Because brigatinib has been associated with bradycardia, caution is advised when brigatinib is used concurrently with other drugs known to cause bradycardia.1 Heart rate should be monitored more frequently if such concomitant use cannot be avoided.1 If clinically important bradycardia occurs with concomitant use of brigatinib and drugs known to cause bradycardia (including antihypertensive agents), the dosage of the concomitant drug should be adjusted or the concomitant drug should be discontinued, if possible.1
Concomitant use of brigatinib and hormonal contraceptives, which are CYP3A substrates, may result in decreased plasma concentrations and reduced efficacy of the hormonal contraceptive.1 Women of childbearing potential should therefore use effective nonhormonal contraception during brigatinib therapy and for at least 4 months after the drug is discontinued.1
Grapefruit products are CYP3A inhibitors and should be avoided because of the potential for increased plasma brigatinib concentrations during concurrent use.1
Brigatinib, an inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase (ALK), c-ros oncogene-1 (ROS-1), insulin-like growth factor receptor-1 (IGFR-1), and fms-like tyrosine kinase 3 (FLT-3) as well as epidermal growth factor receptor (EGFR) deletion and point mutations, is an antineoplastic agent.1, 6, 7, 8, 9, 11 The drug inhibits autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins signal transducer and activator of transcription 3 (STAT3), AKT serine/threonine kinase, extracellular signal-regulated kinase (ERK) 1/2, and ribosomal protein S6 in vitro and in vivo.1
Activating mutations or translocations of the ALK gene have been identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).2, 6, 8, 9, 10, 11 Such ALK gene rearrangements have been identified in approximately 3-7% of patients with non-small cell lung cancer (NSCLC).2, 6, 8, 9, 10 Formation of ALK fusion proteins such as EML4-ALK results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.9, 10, 11
Although the ALK inhibitor crizotinib has demonstrated improved outcomes in patients with NSCLC harboring ALK mutations, secondary resistance to crizotinib eventually develops, generally within the first 1-2 years of treatment.2, 6, 8, 9, 11 Clinical resistance to crizotinib has been attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways.2, 6, 8, 9, 11 Secondary mutations of ALK are responsible for about 30% of cases of acquired crizotinib resistance and gene amplification is implicated in 9% of these cases.6, 7, 11 The CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF;2, 6, 8, 9, 11 development and/or progression of brain metastases occurs in approximately one-half of patients during crizotinib treatment.6, 8
In vitro, brigatinib is approximately 12-fold more potent than crizotinib in its activity against native ALK-positive cell lines6 and is active against cell lines expressing EML4-ALK and nucleophosmin (NPM)-ALK fusion proteins and many mutant forms associated with resistance to alectinib, ceritinib, and/or crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y.1, 6, 7 Brigatinib also demonstrated dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts that expressed EML4-ALK, including those with the crizotinib resistance-conferring L1196M mutation and the G1202R mutation that also confers resistance to ceritinib and alectinib.1, 6, 8 In addition, brigatinib reduced tumor burden and prolonged survival in mice bearing intracranial ALK-positive NSCLC tumor xenografts.1, 6 Brigatinib also has demonstrated antitumor activity in patients with crizotinib-resistant disease and baseline CNS metastases.1, 2
Systemic exposure to brigatinib is dose proportional over the oral dosage range of 60-240 mg following single or multiple doses.1 Following oral administration, peak plasma concentrations of brigatinib are achieved in 1-4 hours.1 Administration of brigatinib with a high-fat meal decreases peak plasma concentrations of brigatinib by 13% but has no effect on systemic exposure compared with administration in the fasting state.1 Brigatinib is 66% bound to plasma proteins and binding is independent of drug concentration.1 Brigatinib is primarily metabolized by cytochrome P-450 (CYP) isoenzymes 2C8 and 3A4; its major active metabolite, AP26123, inhibits ALK with approximately threefold lower potency than the parent drug.1 Steady-state systemic exposure of AP26123 is less than 10% of the parent drug.1 Following oral administration of radiolabeled brigatinib, 65% of the dose is eliminated in feces (41% as unchanged drug) and 25% of the dose is eliminated in urine (86% as unchanged drug).1 The mean elimination half-life of brigatinib is 25 hours.1 Age, gender, race, body weight, and serum albumin concentration do not have clinically important effects on the pharmacokinetics of brigatinib.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Brigatinib can only be obtained through a limited network of specialty pharmacies.12 Consult manufacturer's website for specific information regarding distribution of the drug.12
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions April 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Ariad Pharmaceuticals, Inc. Alunbrig® (brigatinib) tablets prescribing information. Cambridge, MA; 2022 Feb. [Web]
2. Kim DW, Tiseo M, Ahn MJ 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. [PubMed 28475456]
3. Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA website. [Web]
4. Markham A. Brigatinib: First Global Approval. Drugs . 2017; 77:1131-1135. [PubMed 28597393]
5. ALTA-1L study: a phase 3 study of brigatinib versus crizotinib in ALK-positive advanced non-small cell lung cancer patients (ALTA-1L). From ClinicalTrials.gov registry. Accessed 2017 Sep 14. [Web]
6. Zhang S, Anjum R, Squillace R et al. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res . 2016; 22:5527-5538. [PubMed 27780853]
7. Sabari JK, Santini FC, Schram AM et al. The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers. Onco Targets Ther . 2017; 10:1983-1992. [PubMed 28435288]
8. Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol . 2016; 8:32-47. [PubMed 26753004]
9. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol . 2014; 12:429-39. [PubMed 25322323]
10. Sasaki T, Jänne PA. New strategies for treatment of ALK-rearranged non-small cell lung cancers. Clin Cancer Res . 2011; 17:7213-8. [PubMed 22010214]
11. Wu J, Savooji J, Liu D. Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol . 2016; 9:19. [PubMed 26951079]
12. Biologics, Inc. Alunbrig (brigatinib) approved for the treatment of ALK+ metastatic non-small cell lung cancer, available for order at Biologics, Inc. Press release. 2017 May 11. From McKesson Specialty Health website. Accessed 2018 Jan 26. [Web]
13. Camidge DR, Kim HR, Ahn MJ et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med . 2018; 379:2027-2039. [PubMed 30280657]
14. 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; 16:2091-2108. [PubMed 34537440]
35. Hanna NH, Robinson AG, Temin S et al. Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. J Clin Oncol . 2021; 39:1040-1091. [PubMed 33591844]