Introduction
Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinase inhibitor developed for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). This oral targeted therapy represents a significant advancement in managing resistant disease following progression on earlier-generation ALK inhibitors.
Mechanism of Action
Lorlatinib selectively inhibits ALK and ROS1 tyrosine kinases through competitive binding to the ATP-binding site. It demonstrates potent activity against both wild-type ALK and various ALK resistance mutations that develop following treatment with first and second-generation ALK inhibitors, particularly the G1202R mutation. The drug also effectively crosses the blood-brain barrier, providing central nervous system activity against brain metastases.
Indications
Lorlatinib is FDA-approved for:
- Treatment of ALK-positive metastatic NSCLC in patients who have progressed on:
- Crizotinib and at least one other ALK inhibitor, or - Alectinib as first-line ALK inhibitor therapy, or - Ceritinib as first-line ALK inhibitor therapy
Dosage and Administration
Standard dosing: 100 mg orally once daily Administration: With or without food. Tablets should be swallowed whole with water. Dose modifications:- Hepatic impairment (Child-Pugh B): Reduce to 75 mg once daily
- Hepatic impairment (Child-Pugh C): Reduce to 50 mg once daily
- Renal impairment (eGFR <30 mL/min): Reduce to 75 mg once daily
- Management of adverse reactions: Dose reduction to 75 mg or 50 mg once daily may be required
Pharmacokinetics
Absorption: Median Tmax is 1.2 hours. High-fat meal decreases AUC by 14% and Cmax by 21%. Distribution: Apparent volume of distribution is 305 L. Protein binding is 66%. Metabolism: Primarily metabolized by CYP3A4 and UGT1A4. Elimination: Half-life is approximately 24 hours. 48% excreted in feces (unchanged) and 41% in urine (mostly metabolites).Contraindications
- Hypersensitivity to lorlatinib or any component of the formulation
- Concurrent use with strong CYP3A inducers (e.g., rifampin, phenytoin, St. John's wort)
Warnings and Precautions
Serious adverse reactions:- Hyperlipidemia: Significant elevations in cholesterol and triglycerides requiring lipid-lowering agents
- Central nervous system effects: Seizures, cognitive impairment, mood disorders, speech impairment
- Atrioventricular block: May require pacemaker implantation
- Interstitial lung disease/pneumonitis: Monitor for respiratory symptoms
- Hypertension: Monitor blood pressure regularly
- Pancreatitis: Monitor lipase and amylase
- Hepatotoxicity: Monitor liver function tests
- Embryo-fetal toxicity: Can cause fetal harm
Drug Interactions
Strong CYP3A inducers: Contraindicated (significantly decrease lorlatinib exposure) Strong CYP3A inhibitors: Avoid concomitant use (increase lorlatinib exposure) Moderate CYP3A inhibitors: Reduce lorlatinib dose to 75 mg once daily CYP3A substrates: Lorlatinib may decrease exposure to drugs metabolized by CYP3A (e.g., midazolam) P-gp substrates: Lorlatinib may increase exposure to P-gp substrates (e.g., digoxin)Adverse Effects
Most common (≥20%):- Hypercholesterolemia (70%)
- Hypertriglyceridemia (64%)
- Edema (43%)
- Peripheral neuropathy (30%)
- Weight gain (24%)
- Cognitive effects (21%)
- Mood disorders (21%)
- Severe hyperlipidemia
- CNS effects (seizures, psychosis)
- AV block
- Interstitial lung disease
- Pancreatitis
- Hepatotoxicity
Monitoring Parameters
Baseline:- Complete blood count
- Comprehensive metabolic panel
- Lipid panel
- ECG
- Pregnancy testing
- Neurological assessment
- Lipid panel: Every 2 weeks for first 3 months, then monthly
- Liver function tests: Monthly
- ECG: Periodically
- Blood pressure: Regularly
- Neurological and psychiatric status: Regularly
- Signs/symptoms of respiratory toxicity: Continuously
Patient Education
- Take medication at the same time each day with or without food
- Swallow tablets whole; do not crush or chew
- Report any new or worsening neurological symptoms (seizures, memory problems, mood changes)
- Immediately report chest pain, palpitations, or dizziness
- Monitor for signs of liver problems (jaundice, dark urine, abdominal pain)
- Use effective contraception during treatment and for several months after completion
- Inform all healthcare providers about lorlatinib use
- Avoid grapefruit and Seville oranges during treatment
- Report all medications, including over-the-counter drugs and supplements
References
1. Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018-2029. 2. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654-1667. 3. FDA. LORBRENA® (lorlatinib) prescribing information. 2021. 4. Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016;6(10):1118-1133. 5. Huber RM, Hansen KH, Paz-Ares Rodríguez L, 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(12):2091-2108.