Brigatinib

Brigatinib is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and the insulin-like growth factor 1 receptor (IGF-1R). In ALK-positive non-small cell lung cancer (NSCLC), the tumour cells carry an ALK fusion protein such as EML4-ALK that drives their growth. Brigatinib blocks that signal, including in some mutant forms that have become resistant to other ALK inhibitors.

Mechanism of Action

• ALK inhibition: brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivo assays.
• Antitumour activity: it inhibited the in vitro proliferation of cell lines expressing the EML4-ALK and NPM-ALK fusion proteins, and inhibited the growth of EML4-ALK-positive NSCLC xenografts in mice in a dose-dependent way.
• Resistance mutations: it inhibited the in vitro and in vivo viability of cells expressing mutant forms of EML4-ALK linked to resistance to ALK inhibitors, including G1202R and L1196M.
• Active metabolite: the N-desmethyl metabolite AP26123 inhibited ALK with about 3-fold lower potency than brigatinib, and its plasma exposure at steady state was below 10% of that of brigatinib.
• Cardiac electrophysiology: in 123 patients with advanced malignancies given 30 to 240 mg once daily, the largest mean change in QTcF from baseline was below 10 msec, and the exposure-QT analysis suggested no concentration-dependent QTc prolongation.

Pharmacokinetics

• Absorption: the median time to peak concentration is 1–4 hours. Exposure is dose-proportional across 60–240 mg once daily, with modest accumulation on repeated dosing (geometric mean accumulation ratio 1.9–2.4). At steady state, geometric mean Cmax was 552 ng/mL at 90 mg and 1,452 ng/mL at 180 mg once daily, and AUC0-τ was 8,165 and 20,276 h × ng/mL. Brigatinib is a substrate of the transporters P-glycoprotein and BCRP. A high-fat meal lowered Cmax by 13% with no effect on AUC, so tablets can be taken with or without food.
• Distribution: brigatinib is moderately bound (91%) to human plasma proteins, independent of concentration. The blood-to-plasma concentration ratio is 0.69. At 180 mg once daily the apparent volume of distribution at steady state was 307 L, indicating moderate tissue distribution.
• Metabolism: in vitro, brigatinib is metabolised mainly by CYP2C8 and CYP3A4, and to a much lesser extent by CYP3A5. N-demethylation and cysteine conjugation are the two major pathways. Unchanged brigatinib made up 92% of circulating radioactivity after a radiolabelled dose, with AP26123 at 3.5%.
• Elimination: at steady state on 180 mg once daily, apparent oral clearance was 8.9 L/h and the median plasma half-life 24 hours. Excretion is mainly in the faeces (about 65% of a radiolabelled dose, against about 25% in urine). Of the radioactivity recovered in urine and faeces together, 48% was unchanged brigatinib, 27% AP26123 and 9.1% the cysteine conjugate.
• Special populations: in severe hepatic impairment (Child-Pugh C) and in severe renal impairment (eGFR below 30 mL/min), a lower starting dose is recommended (see Administration and Dosage and SmPC section 5.2).

Brigatinib is used alone (monotherapy) in adults with advanced non-small cell lung cancer (NSCLC) that is ALK-positive:

• No previous ALK inhibitor: ALK-positive advanced NSCLC previously not treated with an ALK inhibitor.
• After crizotinib: ALK-positive advanced NSCLC previously treated with crizotinib.

ALK-positive status must be known before treatment starts, using a validated ALK assay.

• Hypersensitivity to brigatinib or to any of the excipients.

The data come from 274 patients treated at the recommended dosing regimen in three trials (median exposure 21.8 months). The most common reactions (≥25%) were increased AST, increased CPK, hyperglycaemia, increased lipase, hyperinsulinaemia, diarrhoea, increased ALT, increased amylase, anaemia, nausea, fatigue, hypophosphataemia, decreased lymphocyte count, cough, increased alkaline phosphatase, rash, increased APTT, myalgia, headache, hypertension, decreased white blood cell count, dyspnoea and vomiting. The most common serious reactions (≥2%), apart from events related to tumour progression, were pneumonia, pneumonitis, dyspnoea and pyrexia.

Very common (≥1/10): pneumonia, upper respiratory tract infection, anaemia, decreased lymphocyte, white blood cell and neutrophil counts, increased APTT, hyperglycaemia, hyperinsulinaemia, hypophosphataemia, hypomagnesaemia, hypercalcaemia, hyponatraemia, hypokalaemia, decreased appetite, headache, peripheral neuropathy, dizziness, visual disturbance, hypertension, cough, dyspnoea, increased lipase and amylase, diarrhoea, nausea, vomiting, abdominal pain, constipation, stomatitis, increased AST, ALT and alkaline phosphatase, rash, pruritus, increased blood CPK, myalgia, arthralgia, increased blood creatinine, fatigue, oedema, pyrexia.

Common (≥1/100 to <1/10): decreased platelet count, insomnia, memory impairment, dysgeusia, bradycardia, QT interval prolongation, tachycardia, palpitations, pneumonitis, dry mouth, dyspepsia, flatulence, increased lactate dehydrogenase, hyperbilirubinaemia, dry skin, photosensitivity, musculoskeletal chest pain, pain in extremity, musculoskeletal stiffness, non-cardiac chest pain, chest discomfort, pain, increased blood cholesterol, weight decreased.

Uncommon (≥1/1,000 to <1/100): pancreatitis.

Reactions that need particular attention are severe, life-threatening or fatal pulmonary reactions (interstitial lung disease or pneumonitis, mostly in the first 7 days), hypertension, bradycardia, visual disturbance, raised CPK, lipase and amylase, hepatotoxicity, hyperglycaemia and photosensitivity (see Special Instructions).

Brigatinib is metabolised mainly by CYP2C8 and CYP3A4, so strong modulators of CYP3A change its exposure.

• Strong CYP3A inhibitors (for example indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, troleandomycin, ketoconazole, voriconazole, nefazodone): itraconazole raised brigatinib AUC about 2-fold (101%) and Cmax by 21%. Avoid the combination; if it cannot be avoided, reduce the brigatinib dose by about 50% (180 mg to 90 mg, or 90 mg to 60 mg). After the inhibitor is stopped, return to the dose tolerated before it.
• Moderate CYP3A inhibitors (for example diltiazem, verapamil): a modelling study suggested a rise in AUC of about 40%. No dose change is needed, but monitor closely.
• CYP3A inducers: avoid strong and moderate inducers. If a moderate inducer cannot be avoided, the brigatinib dose may be raised in 30 mg steps after 7 days at the current tolerated dose, up to twice the dose tolerated before the inducer; after the inducer is stopped, resume the earlier dose. St John’s wort induces CYP3A and should be avoided.
• Grapefruit: grapefruit and grapefruit juice inhibit CYP3A and may raise brigatinib concentrations; avoid them.
• Medicines that slow the heart rate: use caution with other agents known to cause bradycardia, and monitor heart rate and blood pressure more often if the combination cannot be avoided.
• Other pathways: brigatinib is also a substrate of CYP2C8 and of P-glycoprotein and BCRP; SmPC section 4.5 gives the remaining interaction recommendations.

Treatment should be started and supervised by a physician experienced in anticancer medicinal products. ALK-positive NSCLC status must be known first, using a validated ALK assay in a laboratory with proven proficiency. The tablets are swallowed whole with water, with or without food. Grapefruit and grapefruit juice should be avoided.

Recommended Dose

• 90 mg once daily for the first 7 days, then 180 mg once daily.
• Treatment continues as long as clinical benefit is observed.
• If treatment is interrupted for 14 days or longer for reasons other than adverse reactions, restart at 90 mg once daily for 7 days before returning to the previously tolerated dose.

Dose Adjustments for Side Effects

• Dose reduction levels: from 180 mg once daily, reduce to 120 mg, then 90 mg, then 60 mg once daily. During the first 7 days at 90 mg, the reduction is to 60 mg once daily and then permanent discontinuation. Treatment is permanently stopped if 60 mg once daily is not tolerated.
• Interstitial lung disease or pneumonitis: for grade 1, withhold until recovery to baseline, then resume at the same dose level; for grade 2, resume at the next lower dose level. If the event occurs in the first 7 days, do not escalate to 180 mg. Recurrence, or any grade 3 or 4 event, requires permanent discontinuation.
• Hypertension: for grade 3, withhold until grade 1 or lower (systolic below 140 mmHg and diastolic below 90 mmHg), then resume at the same dose; if it recurs, resume at the next lower dose level or discontinue. For grade 4, withhold until grade 1 or lower, then resume at the next lower dose level or discontinue; permanently discontinue if grade 4 recurs.
• Bradycardia (heart rate below 60 bpm): if symptomatic, withhold until the patient is asymptomatic or the resting rate is 60 bpm or more. Resume at the same dose if a contributing medicine is found and stopped or adjusted, otherwise at the next lower dose level. For life-threatening bradycardia, resume at the next lower dose level only if a contributing medicine is found and stopped or adjusted; otherwise, or on recurrence, discontinue permanently.
• Raised CPK: for grade 3 or 4 (above 5.0 times the upper limit of normal, ULN) with grade 2 or higher muscle pain or weakness, withhold until recovery to grade 1 (2.5 × ULN or less) or baseline, then resume at the same dose; if it recurs, resume at the next lower dose level.
• Raised lipase or amylase: for grade 3 (above 2.0 × ULN), withhold until grade 1 (1.5 × ULN or less) or baseline, then resume at the same dose; if it recurs, resume at the next lower dose level. For grade 4 (above 5.0 × ULN), withhold until grade 1, then resume at the next lower dose level.
• Hepatotoxicity: for grade 3 or higher ALT or AST (above 5.0 × ULN) with bilirubin 2 × ULN or less, withhold until recovery to baseline or 3 × ULN or less, then resume at the next lower dose. ALT or AST above 3 × ULN with total bilirubin above 2 × ULN, without cholestasis or haemolysis, requires permanent discontinuation.
• Hyperglycaemia (grade 3 or higher, above 250 mg/dL or 13.9 mmol/L): if optimal medical management does not achieve control, withhold until it is controlled, then resume at the next lower dose or discontinue.
• Visual disturbance: for grade 2 or 3, withhold until grade 1 or baseline, then resume at the next lower dose level. Grade 4 requires permanent discontinuation.
• Other reactions: for grade 3, withhold until baseline and resume at the same dose; if it recurs, resume at the next lower dose level or discontinue. For grade 4, withhold until baseline and resume at the next lower dose level; if it recurs, resume at the next lower dose level or discontinue.

With Strong CYP3A Inhibitors or Moderate CYP3A Inducers

If a strong CYP3A inhibitor cannot be avoided, reduce the dose by about 50% (180 mg to 90 mg, or 90 mg to 60 mg) and return to the previous dose after the inhibitor is stopped. For a moderate CYP3A inducer that cannot be avoided, see Drug Interactions.

Special Populations

• Elderly: no dose adjustment is needed from limited data in patients aged 65 and older; there are no data over 85 years.
• Hepatic impairment: no adjustment in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. In severe impairment (Child-Pugh C), start at 60 mg once daily for 7 days, then 120 mg once daily.
• Renal impairment: no adjustment in mild or moderate impairment (eGFR 30 mL/min or more). In severe impairment (eGFR below 30 mL/min), start at 60 mg once daily for 7 days, then 90 mg once daily, with close monitoring for new or worsening respiratory symptoms, particularly in the first week.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed or Vomited Dose

Do not take an extra dose. Take the next dose at the scheduled time.

Pulmonary Adverse Reactions

Severe, life-threatening and fatal pulmonary reactions, including interstitial lung disease (ILD) or pneumonitis, can occur. Most appeared in the first 7 days; grade 1–2 events resolved with interruption or dose change, and some patients developed pneumonitis later. Older age and an interval of less than 7 days between the last crizotinib dose and the first brigatinib dose were independently linked to a higher rate. Patients with a history of ILD or drug-induced pneumonitis were excluded from the pivotal trials. Patients should be monitored for new or worsening respiratory symptoms (dyspnoea, cough), particularly in the first week. If pneumonitis is suspected, the dose is withheld and other causes (pulmonary embolism, tumour progression, infectious pneumonia) are excluded.

Hypertension and Bradycardia

Blood pressure and heart rate should be monitored regularly, and hypertension treated according to standard guidelines. Heart rate should be monitored more often if a medicine known to cause bradycardia cannot be avoided. For symptomatic bradycardia, brigatinib is withheld and the concomitant medicines are reviewed.

Visual Disturbance and CPK Elevation

Patients should report any visual symptoms; for new or worsening severe symptoms, an eye examination and dose reduction should be considered. Patients should also report unexplained muscle pain, tenderness or weakness, and CPK is monitored regularly.

Pancreatic Enzymes, Liver and Blood Sugar

Lipase and amylase are monitored regularly. Liver function (AST, ALT and total bilirubin) is assessed before starting and then every 2 weeks during the first 3 months, and periodically afterwards. Fasting serum glucose is checked before starting and monitored periodically; antihyperglycaemic treatment is started or optimised as needed.

Photosensitivity

Patients should avoid prolonged sun exposure during treatment and for at least 5 days after stopping. Outdoors they should wear a hat and protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF 30 or higher). For severe reactions (grade 3 or higher), brigatinib is withheld until recovery to baseline.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective non-hormonal contraception during treatment and for at least 4 months after the last dose. Men with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the last dose.
• Pregnancy: brigatinib may cause foetal harm, and animal studies showed reproductive toxicity. There are no clinical data in pregnant women. It should not be used in pregnancy unless the mother’s condition requires it, and the patient should be told of the possible hazard to the foetus.
• Breastfeeding: it is unknown whether brigatinib passes into human milk, and this cannot be excluded. Breastfeeding should be stopped during treatment.
• Fertility: there are no human data. Animal repeat-dose studies suggest that brigatinib may reduce male fertility; the clinical relevance is unknown.

Lactose and Sodium

The tablets contain lactose monohydrate (56 mg, 168 mg and 336 mg in the 30 mg, 90 mg and 180 mg tablets). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Brigatinib has a minor influence on the ability to drive and use machines. Caution is needed because visual disturbance, dizziness or fatigue may occur.

Alunbrig tablets do not require any special storage conditions, and no cold chain is needed. Keep them out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on restricted medical prescription (Annex II B), prescribed by a specialist experienced in anticancer therapy. Brigatinib is taken at home as tablets, so it is supplied to the patient or to the treating clinic on prescription.