Lorlatinib

Lorlatinib is an oral targeted anticancer medicine belonging to the third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor class. It is used to treat advanced or metastatic non-small cell lung cancer (NSCLC) in patients whose tumours have an ALK gene rearrangement. These genetic changes produce abnormal ALK signalling that promotes cancer cell growth and survival. Lorlatinib inhibits ALK and also targets ROS1, another related protein involved in certain cancers. Its ability to reach the central nervous system makes it particularly relevant for patients at risk of, or living with, brain metastases. By blocking abnormal signalling pathways, lorlatinib can slow cancer progression and help control disease in eligible patients. It is supplied as oral tablets and is generally taken once daily, with or without food. Treatment selection requires confirmation of ALK-positive disease using an appropriate validated diagnostic test. The medicine may be used as initial treatment or after progression on other ALK inhibitors, depending on the approved indication and local guidelines. Lorlatinib can cause changes in blood lipid levels, swelling, weight gain, nerve symptoms, and effects on mood or thinking, so regular monitoring is important. Treatment is supervised by an oncology specialist, who assesses response, tolerability, and the need for dose adjustments.

Lorlatinib was developed as a potent, brain-penetrant ALK and ROS1 tyrosine kinase inhibitor designed to address resistance mechanisms that can develop during treatment with earlier ALK inhibitors. The US Food and Drug Administration (FDA) granted accelerated approval on 2 November 2018 for adults with ALK-positive metastatic NSCLC whose disease had progressed after specified earlier ALK inhibitor therapies. The FDA subsequently expanded its indication to include first-line treatment of metastatic ALK-positive NSCLC in 2021. The European Medicines Agency (EMA) granted marketing authorisation for Lorviqua in the European Union on 6 May 2019, with its approved indications covering selected adults with advanced ALK-positive NSCLC. Clinical evidence includes an early-phase multicohort study in previously treated patients and the phase 3 CROWN trial, which compared lorlatinib with crizotinib in previously untreated advanced ALK-positive NSCLC. The CROWN study demonstrated substantial disease-control benefits, including activity against central nervous system disease. Approval conditions and treatment eligibility vary by jurisdiction, so current local prescribing information should be checked before treatment.

Lorlatinib is indicated for the treatment of adults with ALK-positive advanced or metastatic non-small cell lung cancer, with the precise approved indication depending on the country. It may be prescribed as first-line treatment for eligible patients or for disease that has progressed following previous ALK inhibitor therapy. ALK positivity must be confirmed through an appropriate diagnostic test before treatment begins. Lorlatinib is generally used as monotherapy rather than routinely combined with another ALK inhibitor. Its activity against cancer involving the central nervous system makes it a relevant treatment option for selected patients with brain metastases. Treatment decisions consider previous therapies, tumour characteristics, disease progression, overall health, and the patient's ability to tolerate treatment. The medicine is not intended for unselected lung cancers without the required molecular alteration, and treatment should be directed by an oncologist experienced in targeted cancer therapies.

Lorlatinib is administered orally as tablets and can generally be taken with or without food. The standard adult dose is 100 mg once daily, continued until disease progression or unacceptable toxicity. Tablets should be swallowed according to the product instructions and taken consistently at approximately the same time each day. If a dose is missed, patients should follow the prescribing instructions and should not take an additional dose to compensate for a missed one. Dose interruption or reduction may be necessary for adverse reactions or interactions. Reduced doses may be required in patients with severe renal impairment or severe hepatic impairment, according to the applicable prescribing information. Certain interacting medicines may also require dose adjustments or avoidance. Treatment duration is individualised according to response and tolerability. Regular assessment of blood lipids, blood pressure, blood glucose, neurological symptoms, and other clinically relevant parameters helps guide ongoing treatment.

Common side effects of lorlatinib include increased cholesterol and triglyceride levels, swelling of the arms or legs, weight gain, peripheral neuropathy, fatigue, shortness of breath, joint pain, diarrhoea, cough, and changes in mood or cognitive function. Cognitive effects may include difficulties with memory, attention, speech, or concentration. Some patients may experience sleep disturbances or changes in their usual behaviour. Blood lipid abnormalities are particularly common and may require treatment with lipid-lowering medicines. The severity of adverse effects varies among patients and may depend on other medical conditions and concurrent medicines. Patients should report persistent or worsening symptoms to their oncology team rather than stopping treatment independently. Supportive care, laboratory monitoring, and dose modification can help manage many treatment-related effects.

Lorlatinib can cause serious central nervous system effects, including significant changes in mood, behaviour, cognition, speech, or mental status. Other important risks include severe hyperlipidaemia, atrioventricular block and other cardiac conduction abnormalities, hypertension, hyperglycaemia, and interstitial lung disease or pneumonitis. Severe liver toxicity may occur when lorlatinib is taken with certain strong CYP3A inducers. These combinations must be avoided according to prescribing guidance. The medicine can also harm an unborn baby, and effective contraception is required for patients with reproductive potential as directed by the prescribing information. Breastfeeding is not recommended during treatment. New or worsening breathing difficulties, marked confusion, severe mood changes, fainting, or symptoms of significant cardiovascular complications require prompt medical assessment. Lorlatinib may need to be withheld, reduced, or permanently discontinued when serious toxicity develops, depending on its severity and the applicable prescribing recommendations.

Before starting lorlatinib, clinicians should confirm ALK-positive disease and review the patient's medication history, cardiovascular health, neurological status, liver and kidney function, blood pressure, blood glucose, and lipid profile. Cholesterol and triglycerides should be assessed before treatment and monitored regularly because substantial increases may occur. Blood pressure and glucose should also be monitored during therapy. Lorlatinib interacts with drug-metabolising enzymes and transporters, which can alter the effectiveness or toxicity of other medicines. Strong CYP3A inducers are contraindicated because of the risk of serious liver toxicity, while strong CYP3A inhibitors and certain other interacting medicines may require avoidance or dose adjustment. Lorlatinib can reduce the effectiveness of some hormonal contraceptives, so an effective non-hormonal contraceptive method should be discussed with the treating clinician. Patients should inform their healthcare team before starting any prescription medicine, over-the-counter product, or herbal supplement. Pregnancy, breastfeeding, and fertility considerations should be addressed before treatment begins.

Prescribers should confirm the tumour's ALK status before initiating lorlatinib and document baseline lipid levels, blood pressure, glucose, neurological status, and relevant cardiac history. Establish a monitoring schedule for lipid abnormalities early in treatment and initiate appropriate lipid-lowering therapy when indicated. Review the full medication list for CYP3A-related interactions and medicines that may affect cardiac conduction. Counsel patients and caregivers about possible cognitive, mood, or behavioural changes, including symptoms that should be reported promptly. Reinforce adherence to once-daily dosing and explain the importance of not doubling a missed dose. Pharmacists should verify the prescribed strength, dose modifications, storage requirements, and interaction risks whenever a new medicine is introduced. Assess treatment tolerance regularly and coordinate with the oncology team regarding laboratory abnormalities, dose interruptions, or reductions. Patients should understand that treatment continues while it provides benefit and remains tolerable, and that any changes to therapy must be guided by their treating specialist.