brigatinib

Brigatinib is an oral medication used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in adults.

Cancers are caused by gene mutations that lead to uncontrolled growth and replication of abnormal cells that do not function normally and suppress the growth and activity of normal cells. Brigatinib is a small molecule targeted therapy drug that does not kill cancer cells, but specifically targets the abnormal cells and alters cell mechanisms to prevent the growth and spread of cancer.

Brigatinib works by inhibiting the activity of several proteins known as tyrosine kinases, including abnormal ALK fusion proteins that go out of control because of certain gene mutations and promote the growth and proliferation of cancer cells. Other tyrosine kinases that brigatinib inhibits include ROS1, insulin-like growth factor-1 receptor (IGF-1R), FMS-like tyrosine kinase 3 (FLT-3), and epidermal growth factor receptor (EGFR) deletion and point gene mutations.

ALK is an enzyme coded by the ALK gene which helps in the development of the fetal gastrointestinal and nervous systems. The ALK gene is normally turned off in the fetal stage, but in some people, it gets turned on later and fuses with other genes and generates abnormal ALK fusion proteins. ALK fusion proteins alter cell signaling and gene expression, which results in the proliferation and survival of tumor cells that express this protein. Brigatinib inhibits the activity of ALK and ALK-mediated activation of downstream signaling protein STAT3.

Brigatinib targets cancer cells that express ALK fusion proteins, including EML4-ALK and 17 mutant forms associated with resistance to other ALK inhibitor drugs, including crizotinib. Brigatinib also inhibits other mutant proteins including EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib is approved for use only in the treatment of NSCLCs that are positive for ALK fusion proteins as detected by an FDA-approved test.

• Brigatinib treatment has been known to cause severe, life-threatening or fatal interstitial lung disease (ILD)/lung inflammation (pneumonitis) in some patients.
  • Monitor patients for new or worsening of respiratory symptoms, particularly in the first week of treatment.
  • Withhold brigatinib and evaluate patients with new or worsening pulmonary symptoms for ILD/pneumonitis or other causes.
  • Resume treatment at a lower dose or permanently discontinue brigatinib based on the condition of the patient, as recommended.
• There have been reports of hypertension in patients treated with brigatinib.
  • Control blood pressure before starting treatment, and monitor blood pressure after 2 weeks of initiating brigatinib and at least once a month thereafter.
  • Use brigatinib with caution when administering along with antihypertensive drugs that can slow down the heart rate (bradycardia).
  • If hypertension is not controlled with optimal treatment, withhold brigatinib until condition improves and resume treatment, or discontinue permanently as appropriate.
• Brigatinib lowered heart rate to less than 50 bpm in some patients in clinical trials.
  • Monitor heart rate and blood pressure regularly during treatment, and more frequently in patients who need to take drugs that are known to cause bradycardia.
  • For symptomatic bradycardia, withhold brigatinib, identify concomitant drug that causes bradycardia, adjust its dose or discontinue, and resume brigatinib after resolution of bradycardia.
  • Discontinue brigatinib permanently for life-threatening bradycardia, if no other concomitant contributing drug is identified.
• Brigatinib can cause visual disturbances. Advise patient to report any visual symptoms, withhold brigatinib and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms. Resume at reduced dose upon recovery, or permanently discontinue brigatinib as recommended, based on the severity of condition.
• Brigatinib increased creatine phosphokinase (CPK) levels in many patients.
  • Monitor patient’s CPK levels during treatment and advise patients to report any unexplained muscle pain, tenderness or weakness.
  • Withhold brigatinib in patients with elevated CPK levels and muscle symptoms and resume treatment upon recovery at same or reduced dose.
• Brigatinib caused elevation of pancreatic enzymes amylase and lipase in some patients. Monitor levels of amylase and lipase during treatment, withhold brigatinib in patients with elevated levels and resume at same or reduced dose, upon recovery.
• Brigatinib treatment resulted in new onset or worsening of hyperglycemia. Check fasting serum glucose levels before starting treatment, monitor periodically and treat appropriately, in case of hyperglycemia. If adequate glycemic control cannot be achieved, withhold brigatinib and resume at a reduced dose, or discontinue permanently.
• Brigatinib can cause fetal harm.
  • Screen for pregnancy before initiating brigatinib. Avoid use if pregnant because of the potential risk to the fetus.
  • Effective non-hormonal contraception should also be used by males with female partners of reproductive potential to follow effective contraception for the recommended periods.

Serious side effects of brigatinib include:

• Pneumonia
• Interstitial lung disease (ILD)/lung inflammation (pneumonitis)
• Respiratory failure
• Blood clot in lungs (pulmonary embolism)
• Cerebrovascular accident
• Multiple organ dysfunction syndrome
• Bacterial meningitis
• Urosepsis
• Sudden death

Common side effects of brigatinib include:

• Elevated creatine phosphokinase (CPK)
• Increase in liver enzyme aspartate aminotransferase (AST)
• Increase in liver enzyme alanine aminotransferase (ALT)
• Increase in alkaline phosphatase (ALK)
• Increase in pancreatic enzymes lipase and amylase
• High blood glucose levels (hyperglycemia)
• Elevation in blood insulin
• Increase in creatinine levels
• Increase in blood cholesterol
• Reduced albumin levels
• Electrolyte disturbances including:
  • Decrease in phosphorous, magnesium, and calcium
  • Increase in potassium and calcium
  • Low sodium (hyponatremia)
  • Low potassium (hypokalemia)
• Decrease in hemoglobin
• Low count of red blood cells (anemia)
• Decrease in lymphocyte immune cells (lymphopenia)
• Decrease in neutrophil immune cells
• Decrease in platelet count
• Prolonged blood clotting time (activated partial thromboplastin time [aPTT])
• Diarrhea
• Abdominal pain
• Nausea
• Vomiting
• Constipation
• Oral inflammation (stomatitis)
• Indigestion (dyspepsia)
• Gastroesophageal reflux disease (GERD)
• Rash
• Itching (pruritus)
• Dry skin
• Shortness of breath (dyspnea)
• Cough
• Low oxygen saturation in tissue (hypoxia)
• High blood pressure (hypertension)
• Slow heart rate (bradycardia)
• High temperature (pyrexia)
• Weakness (asthenia)
• Fatigue
• Swelling from fluid retention (edema)
• Pain
• Muscle spasms
• Muscle pain (myalgia)
• Joint pain (arthralgia)
• Back pain
• Limb pain
• Musculoskeletal stiffness
• Headache
• Dizziness
• Peripheral nerve damage (neuropathy)
• Taste disorder (dysgeusia)
• Upper respiratory tract infection
• Nose and throat inflammation (nasopharyngitis)
• Urinary tract infection
• Decreased appetite
• Visual disturbance
• Insomnia

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet

• 30 mg
• 90 mg
• 180 mg

Adult:

Non-Small Cell Lung Cancer

• Indicated for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC)
• 90 mg orally once daily for the first 7 days; if 90 mg/day tolerated, increase to 180 mg orally once daily
• Continue until disease progression or unacceptable toxicity

Dosage Modifications

• If treatment is interrupted for 14 days or longer for reasons other than adverse reactions, resume at 90 mg once daily for 7 days before increasing to previously tolerated dose

Dose reductions

• Once discontinued, do not subsequently increase dose
• Permanently discontinue if unable to tolerate 60 mg/day
• 90 mg/day dose
  • First reduction: 60 mg once daily
• 180 mg/day dose
  • First reduction: 120 mg once daily
  • Second reduction: 90 mg once daily
  • Third reduction: 60 mg once daily

Interstitial lung disease/pneumonitis

• Grade 1
  • If new pulmonary symptoms occur during the first 7 days of treatment, withhold until recovery to baseline, then resume at same dose and do not escalate to 180 mg if interstitial lung disease (ILD)/pneumonitis is suspected
  • If new pulmonary symptoms occur after the first 7 days of treatment, withhold until recovery to baseline, then resume at same dose
  • If ILD/pneumonitis recurs, permanently discontinue
• Grade 2
  • If new pulmonary symptoms occur during the first 7 days of treatment, withhold until recovery to baseline; resume at next lower dose and do not escalate dose if ILD/pneumonitis is suspected
  • If new pulmonary symptoms occur after the first 7 days of treatment, withhold until recovery to baseline; if ILD/pneumonitis is suspected, resume at next lower dose; otherwise, resume at same dose
  • If ILD/pneumonitis recurs, permanently discontinue
• Grade 3 or 4
  • Permanently discontinue drug for ILD/pneumonitis

Hypertension

• Grade 3 (systolic blood pressure [SBP] 160 mmHg or higher or diastolic blood pressure [DBP] 100 mmHg or higher)
  • Medical intervention indicated, more than 1 antihypertensive drug, or more intensive therapy than previously used indicated
  • Withhold until hypertension grade 1 or below (SBP below 140 mmHg and DBP below 90 mmHg), then resume at next lower dose
  • Recurrence: Withhold until recovery to grade 1 or below, then resume at next lower dose or permanently discontinue
• Grade 4 (life-threatening, urgent intervention indicated)
  • Withhold until recovery to grade 1 or below and resume at next lower dose or permanently discontinue
  • Recurrence: Permanently discontinue

Bradycardia

• Symptomatic
  • Withhold until recovery to asymptomatic bradycardia or to a resting heart rate (HR) 60 bpm or above
  • Discontinue or adjust dose of concomitant medication known to cause bradycardia, then resume at same dose or to resting HR 60 bpm or above
  • If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume at next lower dose
• Bradycardia with life-threatening, urgent intervention indicated
  • Permanently discontinue if no contributing concomitant medication is identified
  • If contributing concomitant medication is identified and discontinued or dose-adjusted, resume at next lower dose upon recovery to asymptomatic bradycardia or to a resting HR 60 or above, with frequent monitoring as clinically indicated
  • Recurrence: Permanently discontinue

Visual disturbance

• Grade 2 or 3: Withhold until recovery to grade 1 or baseline, then resume at next lower dose
• Grade 4: Permanently discontinue

Creatine phosphokinase (CPK) elevation

• Grade 3 (CPK above 5 times upper limit of normal [ULN]): Withhold drug until recovery to grade 1 or lower (below 2.5 times ULN) or baseline, then resume at same dose
• Grade 4 (CPK above 10 times ULN) or grade 3 recurrence: Withhold until recovery to grade 1 or below or to baseline, then resume at next lower dose

Lipase/amylase elevation

• Grade 3 (lipase or amylase above 2 times ULN): Withhold until recovery to grade 1 or below (1.5 or fewer times ULN) or to baseline, then resume at same dose
• Grade 4 (lipase or amylase above 5 times ULN) or grade 3 recurrence: Withhold until recovery to grade 1 or below or to baseline, then resume at next lower dose

Hepatoxicity

• Grade 3 or 4 (ALT/AST above 5 times ULN with bilirubin 2 or fewer times ULN): Withhold until recovery to Grade 1 or below (3 times ULN) or baseline, then resume at next lower dose
• Grade 2-4 elevation (ALT/AST above 3 times ULN with concurrent total bilirubin above 2 times ULN without cholestasis or hemolysis): Permanently discontinue

Hyperglycemia

• Grade 3 (above 250 mg/dL or 13.9 mmol/L) or 4: if adequate hyperglycemic control not achieved with optimal medical management, withhold therapy until adequate hyperglycemic control attained; resume at next lower dose or permanently discontinue

Other toxicity

• Grade 3
  • Withhold until recovery to baseline, then resume at same dose
  • Recurrence: Withhold until recovery to baseline, then resume at next lower dose or discontinue
• Grade 4
  • First occurrence: Either withhold until recovery to baseline and resume at next lower dose or permanently discontinue
  • Recurrence: Permanently discontinue

Coadministration with strong or moderate CYP3A inhibitors

• Avoid use
• If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce brigatinib dose by approximately 50% (e.g., from 180 mg to 90 mg, or from 90 mg to 60 mg)
• If coadministration of a moderate CYP3A inhibitor cannot be avoided, reduce once daily dose by approximately 40% (e.g., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg)
• After discontinuation of a strong or moderate CYP3A inhibitor, resume brigatinib dose that was previously tolerated before coadministration

Coadministration with moderate CYP3A inducers

• Avoid use
• If coadministration of a moderate CYP3A inducer cannot be avoided, increase once daily dose in 30 mg increments after 7 days of treatment with the current dose as tolerated, up to a maximum of twice the dose that was tolerated before initiating a moderate CYP3A inducer
• After discontinuation of a moderate CYP3A inducer, resume dose that was tolerated before initiating the moderate CYP3A inducer

Hepatic impairment

• Mild or moderate (Child-Pugh A or B): No dose adjustment required
• Severe (Child-Pugh C): Reduce once daily dose by approximately 40% (e.g., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg)

Renal impairment

• Mild or moderate (creatinine clearance [CrCl] 30-89 mL/minute): No dose adjustment required
• Severe (CrCl 15-29 mL/minute): Reduce brigatinib dose by approximately 50% (e.g., from 180 mg to 90 mg, or from 90 mg to 60 mg)

Dosing Considerations

Patient selection

Select patients for treatment of metastatic NSCLC based on ALK-positive tumor specimens

• Information on FDA-approved tests is available at https://www.fda.gov/CompanionDiagnostics.
• Pediatric:

Safety and efficacy not established

Overdose

There is no information available on brigatinib overdose. Overdose will likely intensify the drug’s adverse effects. Overdose may be treated with dose reduction, interruption or discontinuation of brigatinib treatment, and symptomatic and supportive therapy.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of brigatinib include:
  • doravirine
  • lonafarnib
• Brigatinib has serious interactions with at least 110 different drugs.
• Brigatinib has moderate interactions with at least 27 different drugs.
• Mild interactions of brigatinib include:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • larotrectinib

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Brigatinib can cause fetal harm, based on its mechanism of action and findings in animal reproductive studies.
• If you may potentially become pregnant, use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose, because brigatinib may nullify the effects of some hormonal contraceptives.
• Men with reproductive potential who have women partners that can get pregnant should use effective contraception during treatment and for at least 3 months after treatment completion.
• Brigatinib may reduce fertility in men.
• There is no information on the presence of brigatinib in breastmilk or its effects on milk production and the breastfed infant. Avoid breastfeeding during treatment and for 1 week following the final dose, because of the potential for serious adverse reactions in the breastfed infant.

• Take brigatinib exactly as prescribed. Do not take an additional dose if you vomit after taking the drug, but continue with the next scheduled dose.
• Avoid grapefruit, grapefruit juice, and other grapefruit products while on treatment with brigatinib.
• You will need periodic blood and other tests. Follow up with your healthcare provider and do not miss your appointments.
• Brigatinib can raise blood pressure and disturb the heart rhythm. Report to your physician immediately in case of new or worsening symptoms such as chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, fainting, and changes in or new use of heart or blood pressure medications.
• Report to your physician immediately if you experience new onset or worsening of:
  • Respiratory symptoms including shortness of breath (dyspnea) or cough
  • Reduced vision acuity or other visual symptoms
  • Unexplained muscle pain, weakness or tenderness
  • Hyperglycemia symptoms such as increased thirst and urination, tiredness and recurrent infections
• Brigatinib can affect the pancreas. Report to your physician immediately if you develop symptoms of pancreatitis such as upper abdominal pain, nausea, vomiting, bloating, or loss of appetite.
• Store brigatinib safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.