Lorlatinib

Lorlatinib is a selective, ATP-competitive inhibitor of the anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinases. In ALK-positive non-small cell lung cancer (NSCLC) a rearranged ALK gene, for example the EML4-ALK fusion, drives tumour growth. Lorlatinib is active against the non-mutated kinase and against clinically relevant ALK mutations, including some that cause resistance to earlier ALK inhibitors.

Mechanism of Action

• ALK and ROS1 inhibition: lorlatinib blocks the catalytic activity of ALK and ROS1 in enzyme and cell-based assays, and in vitro it also acts on several other tyrosine kinases. Its antitumour activity in animal models was dose-dependent and correlated with inhibition of ALK phosphorylation.
• Resistance mutations: in mice with tumour xenografts expressing EML4-ALK variant 1, lorlatinib was markedly active against the ALK mutations L1196M, G1269A, G1202R and I1171T. G1202R and I1171T are known to cause resistance to alectinib, brigatinib, ceritinib and crizotinib.
• Brain penetration: lorlatinib crosses the blood–brain barrier and was active in mice with orthotopic EML4-ALK or EML4-ALK L1196M brain tumour implants.
• Cardiac conduction: PR interval prolongation is concentration-dependent. In 295 patients on 100 mg daily the maximum mean change from baseline was 16.4 ms (upper 90% confidence limit 19.4 ms); among 284 patients with a baseline PR interval under 200 ms, 14% reached 200 ms or more, and atrioventricular block occurred in 1.0%. No increase in the mean QTc interval was seen in a crossover study in healthy volunteers.

Pharmacokinetics

• Absorption: rapid; median time to peak 1.2 hours after a single 100 mg dose and 2.0 hours with repeated once-daily dosing. Absolute bioavailability is about 81% compared with intravenous dosing. A high-fat, high-calorie meal raised exposure by only 5%, so lorlatinib can be taken with or without food. At 100 mg once daily the geometric mean peak concentration was 577 ng/mL and the AUC over 24 hours 5,650 ng·h/mL.
• Distribution: about 66% bound to human plasma proteins in vitro, with moderate binding to albumin and α1-acid glycoprotein.
• Metabolism: oxidation and glucuronidation, mainly by CYP3A4 and UGT1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5 and UGT1A3. The main plasma metabolite, a pharmacologically inactive benzoic acid derivative, accounts for 21% of circulating radioactivity. Lorlatinib induces its own metabolism (auto-induction), so steady-state exposure is lower than single-dose data predict; it also acts as an inducer through the human PXR and CAR receptors.
• Elimination: plasma half-life after a single 100 mg dose is 23.6 hours, and the effective half-life at steady state after auto-induction about 14.8 hours. Oral clearance is about 17.7 L/h. After a radiolabelled dose, 47.7% of the radioactivity was recovered in urine (under 1% as unchanged lorlatinib) and 40.9% in faeces (9.1% as unchanged lorlatinib).
• Special populations: age, sex, race, body weight and CYP3A5 or CYP2C19 phenotype have no clinically relevant effect. Mild hepatic impairment did not change exposure meaningfully; lorlatinib AUC rose by 15% in moderate and by 82% in severe hepatic impairment. In severe renal impairment (eGFR under 30 mL/min) AUC rose by 41%.

Lorlatinib is indicated as monotherapy for adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC):

• First line: patients previously not treated with an ALK inhibitor.
• After a previous ALK inhibitor: patients whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or after crizotinib and at least one other ALK TKI.

• Hypersensitivity to lorlatinib or to any of the excipients.
• Concomitant use of strong CYP3A4/5 inducers (for example rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St John’s wort).

The most frequently reported adverse reactions in 547 adults on 100 mg once daily (three studies) were hypercholesterolaemia (79.0%), hypertriglyceridaemia (67.5%), oedema (55.4%), peripheral neuropathy (44.2%), fatigue (30.7%), weight increased (29.8%), arthralgia (27.8%), cognitive effects (27.4%), diarrhoea (22.7%) and mood effects (21.4%). Serious adverse reactions occurred in 9.1% of patients, most often cognitive effects and pneumonitis. Dose reductions for adverse reactions were needed by 20.1% (mainly for oedema, cognitive effects and peripheral neuropathy), and 4.0% stopped permanently (mainly for cognitive effects, peripheral neuropathy, pneumonitis and psychotic effects).

Very common (≥1/10): anaemia; hypercholesterolaemia; hypertriglyceridaemia; mood effects; cognitive effects; peripheral neuropathy; headache; vision disorder; hypertension; diarrhoea, nausea and constipation; raised ALT and AST; rash; arthralgia and myalgia; oedema; fatigue; weight increased; raised lipase and amylase.

Common (≥1/100 to <1/10): hyperglycaemia; psychotic effects; mental status changes; speech effects; pneumonitis; proteinuria.

Uncommon (≥1/1,000 to <1/100): PR interval prolongation on the electrocardiogram.

The SmPC groups related terms under one reaction. Cognitive effects include memory impairment, attention disturbance and confusional state; mood effects include irritability, anxiety, depression, affect lability and mood swings; psychotic effects include hallucinations; peripheral neuropathy includes paraesthesia, hypoaesthesia and gait disturbance; oedema includes peripheral oedema and swelling; vision disorder includes diplopia, photophobia and blurred vision.

Grade 3–4 events were most often hypercholesterolaemia (19.2%), hypertriglyceridaemia (20.3%), weight increased (11%), raised lipase (6.8%) and hypertension (6.0%). Other important reactions are effects on the central nervous system, atrioventricular block, a risk of pancreatitis, and interstitial lung disease or pneumonitis (see Special Instructions).

Lorlatinib is metabolised mainly by CYP3A4 and UGT1A4. It is also a moderate inducer of CYP3A and P-glycoprotein, so it can lower the levels of other medicines.

• Strong CYP3A4/5 inducers (rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin, St John’s wort): contraindicated. Rifampicin reduced lorlatinib exposure (AUCinf) by 85% and peak concentration by 76% in healthy volunteers, and raised AST and ALT.
• Moderate CYP3A4/5 inducers: modafinil did not meaningfully change lorlatinib levels or liver tests in healthy volunteers.
• Strong CYP3A4/5 inhibitors (boceprevir, cobicistat, itraconazole, ketoconazole, posaconazole, troleandomycin, voriconazole, ritonavir and ritonavir-boosted combinations): itraconazole raised lorlatinib exposure by 42% and peak concentration by 24%. An alternative with less inhibitory potential should be considered; if a strong inhibitor must be used, lorlatinib is reduced to 75 mg once daily.
• Grapefruit: grapefruit products may raise lorlatinib levels and should be avoided.
• CYP3A4/5 substrates with a narrow therapeutic index: lorlatinib lowered the exposure of a sensitive CYP3A probe substrate by 61% (AUC) and 50% (peak). Combinations with alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus should be avoided.
• Hormonal contraceptives: their levels may fall so far that they become ineffective, so a non-hormonal method is needed (see Special Instructions).
• P-glycoprotein substrates: lorlatinib lowered fexofenadine exposure by 67% (AUC), so P-gp substrates with a narrow therapeutic index, such as digoxin and dabigatran etexilate, need caution.
• Weaker effects: lorlatinib is a weak inducer of CYP2B6, CYP2C9 and UGT enzymes. No dose change is needed for medicines cleared mainly by these routes, but narrow-index CYP2C9 substrates (for example coumarin anticoagulants) and narrow-index UGT substrates should be monitored.
• Transporters: lorlatinib may inhibit BCRP, OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 in vitro, so their substrates should be used with caution.
• Food: lorlatinib can be taken with or without food. Grapefruit and St John’s wort should be avoided.

Treatment should be started and supervised by a physician experienced in the use of anticancer medicinal products. ALK-positive NSCLC must be confirmed first, by a laboratory with proven experience in the technology used, because ALK-positive patients are the only ones in whom benefit has been shown. The tablets are swallowed whole at about the same time each day, with or without food. They must not be chewed, crushed or split, and a broken, cracked or otherwise damaged tablet must not be taken.

Recommended Dose

• 100 mg once daily, continued until disease progression or unacceptable toxicity.

Dose Reductions and Modifications

The dose can be interrupted or reduced according to safety and tolerability. The first reduction is 75 mg once daily and the second 50 mg once daily; treatment is stopped permanently if 50 mg once daily is not tolerated. The main recommendations in the SmPC are:

• Hypercholesterolaemia or hypertriglyceridaemia: for mild to moderate increases (cholesterol up to 400 mg/dL [10.34 mmol/L], triglycerides up to 500 mg/dL [5.7 mmol/L]), start or adjust lipid-lowering therapy and continue lorlatinib at the same dose. For severe increases (cholesterol 401–500 mg/dL [10.35–12.92 mmol/L], triglycerides 501–1,000 mg/dL [5.71–11.4 mmol/L]), start or step up lipid-lowering therapy and continue lorlatinib at the same dose without interruption. For life-threatening increases (cholesterol above 500 mg/dL, triglycerides above 1,000 mg/dL), also step up lipid-lowering therapy, withhold lorlatinib until the level falls to moderate or mild, then restart at the same dose; if severe increases recur despite maximal lipid-lowering therapy, reduce by one dose level.
• Central nervous system effects (psychotic effects and changes in cognition, mood, mental status or speech): grade 2 or 3, withhold until grade 1 or less, then resume at one reduced dose level; grade 4, stop permanently.
• Raised lipase or amylase (grade 3 or 4): withhold until back to baseline, then resume at one reduced dose level.
• Interstitial lung disease or pneumonitis: grade 1 or 2, withhold until symptoms return to baseline, consider corticosteroids and resume at one reduced dose level; stop permanently if it recurs or does not recover after 6 weeks of withholding and steroid treatment. Grade 3 or 4, stop permanently.
• PR interval prolongation or atrioventricular (AV) block: asymptomatic first-degree AV block, continue at the same dose, review concomitant medicines and correct electrolyte imbalance, and monitor closely. Symptomatic first-degree block, withhold and resume at one reduced dose level when symptoms resolve. Asymptomatic second-degree block, withhold and resume at one reduced dose level if a later ECG no longer shows second-degree block. Symptomatic second-degree block, withhold, refer for cardiac observation and consider a pacemaker if it persists; resume at one reduced dose level if symptoms and the second-degree block resolve or revert to asymptomatic first-degree block. Complete AV block, withhold and refer for cardiac observation; a pacemaker may be needed. If a pacemaker is placed, resume at full dose; if not, resume at one reduced dose level only when symptoms resolve and the PR interval is below 200 ms.
• Hypertension: grade 3, withhold until grade 1 or less (systolic below 140 mmHg and diastolic below 90 mmHg) and resume at the same dose; if it recurs, resume at a reduced dose; stop permanently if adequate control cannot be achieved with optimal medical management. Grade 4, withhold until grade 1 or less and resume at a reduced dose or stop permanently; stop permanently if grade 4 recurs.
• Hyperglycaemia (grade 3, or grade 4 with persistent glucose above 250 mg/dL despite optimal therapy): withhold until adequately controlled, then resume at the next lower dose; stop permanently if control cannot be achieved with optimal medical management.
• Other adverse reactions: grade 1 or 2, consider no change or a one-level reduction as clinically indicated; grade 3 or higher, withhold until symptoms are grade 2 or less or at baseline, then resume at one reduced dose level.

With Strong CYP3A4/5 Inhibitors

If a strong CYP3A4/5 inhibitor or grapefruit juice products cannot be avoided, the starting dose of 100 mg once daily is reduced to 75 mg once daily. When the inhibitor is stopped, lorlatinib is resumed at the previous dose after a washout period of 3 to 5 half-lives of the inhibitor.

Special Populations

• Elderly (65 years and older): because data are limited, no dose recommendation can be made.
• Renal impairment: no adjustment for normal renal function or mild to moderate impairment (eGFR 30 mL/min or more). In severe impairment (eGFR under 30 mL/min) a reduced starting dose is recommended, for example 75 mg once daily. There is no information for patients on dialysis.
• Hepatic impairment: no adjustment in mild or moderate impairment. In severe impairment (Child-Pugh C) the starting dose is reduced from 100 mg to 50 mg once daily.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed Dose

Take the missed dose as soon as it is remembered, unless the next dose is due in less than 4 hours; in that case the missed dose is skipped. Never take two doses at the same time to make up for a missed dose.

Hyperlipidaemia

Lorlatinib raises serum cholesterol and triglycerides. The median time to a severe increase was 201 days (range 29–729) for cholesterol and 127 days (range 15–1,367) for triglycerides. Both are measured before starting, 2, 4 and 8 weeks after starting, and regularly afterwards. Lipid-lowering medicines are started or increased if indicated.

Central Nervous System Effects

Psychotic effects and changes in cognitive function, mood, mental status or speech have been seen. Dose modification or discontinuation may be needed.

Atrioventricular Block

The studied population excluded patients with second-degree or third-degree AV block (unless paced) or any AV block with a PR interval above 220 ms. PR interval prolongation and AV block have been reported. An ECG is recorded before starting and monthly afterwards, especially in patients with conditions that predispose to clinically significant cardiac events.

Left Ventricular Ejection Fraction Decrease

Decreases in left ventricular ejection fraction (LVEF) have been reported, but a causal relationship with lorlatinib could not be established. Cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered in patients with cardiac risk factors or conditions that can affect LVEF, and in those who develop relevant cardiac signs or symptoms.

Lipase and Amylase Increase

Lipase and amylase rises have occurred; the median time to onset was 169 days (range 1–1,755) for lipase and 158 days (range 1–1,932) for amylase. Because of concomitant hypertriglyceridaemia and a possible intrinsic mechanism, the risk of pancreatitis should be considered. Lipase and amylase are monitored before treatment and regularly as clinically indicated.

Interstitial Lung Disease and Pneumonitis

Severe or life-threatening pulmonary reactions consistent with ILD or pneumonitis have occurred. Anyone with worsening breathlessness, cough or fever should be evaluated promptly, and lorlatinib is withheld or stopped permanently according to severity.

Hypertension and Hyperglycaemia

Blood pressure should be controlled before starting and checked after 2 weeks and at least monthly afterwards. Fasting serum glucose is assessed before starting and monitored periodically according to national guidelines. In both cases lorlatinib is withheld, reduced or stopped according to severity.

Interacting Medicines

Strong CYP3A4/5 inducers are contraindicated: with rifampicin, healthy volunteers had raised ALT and AST. Medicines with a narrow therapeutic index that depend on CYP3A4/5, including hormonal contraceptives, should be avoided because lorlatinib may lower their concentrations.

Pregnancy, Breastfeeding and Fertility

• Women of childbearing potential: they should avoid becoming pregnant. A highly effective non-hormonal method of contraception is required during treatment, because lorlatinib can make hormonal contraceptives ineffective. If a hormonal method is unavoidable, a condom must be used as well. Effective contraception continues for at least 35 days after the last dose.
• Men: those with female partners of childbearing potential must use effective contraception, including a condom, during treatment and for at least 14 weeks after the last dose; those with pregnant partners must use condoms.
• Pregnancy: animal studies showed embryo-foetal toxicity and there are no data in pregnant women. Lorlatinib may cause foetal harm and is not recommended in pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: it is unknown whether lorlatinib and its metabolites pass into human milk, and a risk to newborns and infants cannot be excluded. Lorlatinib should not be used during breastfeeding, which is stopped during treatment and for 7 days after the last dose.
• Fertility: based on non-clinical findings, male fertility may be compromised, and men should seek advice on fertility preservation before treatment. It is not known whether female fertility is affected.

Lactose and Sodium

The tablets contain lactose (1.58 mg in the 25 mg tablet and 4.20 mg in the 100 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Lorlatinib has a moderate influence on the ability to drive and use machines. Caution is needed because patients may experience effects on the central nervous system.

Lorviqua tablets do not require any special storage conditions. They are supplied in OPA/aluminium/PVC blisters with aluminium foil backing, each holding 10 tablets: packs of 90 tablets (9 blisters) for the 25 mg strength and 30 tablets (3 blisters) for the 100 mg strength; not all pack sizes may be marketed. Keep out of the sight and reach of children.

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

Prescription only (Rx), subject to restricted medical prescription: treatment is started and supervised by a physician experienced in the use of anticancer medicinal products. Lorlatinib is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.