LorlatinibEdit
Lorlatinib is a targeted cancer therapy that belongs to the class of drugs known as tyrosine kinase inhibitors. It is designed to block signaling from the anaplastic lymphoma kinase (anaplastic lymphoma kinase) and, to a lesser extent, ROS1 kinases, with a particular strength in crossing the blood-brain barrier. This makes lorlatinib especially relevant for patients with non-small cell lung cancer that carry ALK rearrangements, a subset of cancers that can spread to the brain. It was developed as part of the broader shift in oncology toward precision medicine, where therapies are chosen based on the specific molecular drivers of a patient’s tumor rather than solely on histology or location.
Lorlatinib has been approved for adults with ALK-positive metastatic non-small cell lung cancer whose disease has progressed on or is intolerant to prior ALK inhibitor therapy. It is marketed under the name LORBRENA in many markets and has been studied in a number of additional settings, including first-line treatment in combination or as a single agent, reflecting ongoing efforts to improve intracranial control and overall outcomes for this group of patients. As a brain-penetrant ALK inhibitor, lorlatinib aims to address a common challenge in ALK-rearranged cancers—metastasis to the central nervous system that limits the effectiveness of earlier generations of ALK inhibitors.
Mechanism of action
Lorlatinib is a selective, potent inhibitor of the ALK kinase and, to a lesser extent, ROS1. By binding to the ATP-binding site of these kinases, it prevents phosphorylation and downstream signaling required for tumor cell growth and survival. Its design emphasizes activity against many ALK resistance mutations that can arise after treatment with earlier ALK inhibitors, and its high brain exposure helps it target tumor cells in the central nervous system. In practice, this dual focus—potent ALK inhibition and robust CNS penetration—drives its use in patients whose disease includes brain metastases or who are at high risk for CNS progression.
The drug is typically discussed in the context of targeted therapy and precision medicine, where tumor profiling guides treatment choices rather than a one-size-fits-all approach. For readers exploring related targets, see anaplastic lymphoma kinase and ROS1 to understand the broader family of kinases lorlatinib engages.
Medical uses and indications
Indication: Lorlatinib is approved for adults with ALK-positive metastatic non-small cell lung cancer whose disease progressed after, or could not tolerate, crizotinib or other prior ALK inhibitors. The labeling reflects its role after resistance to earlier ALK-targeted therapies.
Dosing and administration: The typical starting dose is 100 mg taken orally once daily, with dose adjustments possible for drug interactions or intolerability. Because lorlatinib is primarily metabolized by the liver through the CYP3A4 pathway, concomitant use with strong CYP3A inhibitors or inducers requires careful dose modification or avoidance.
Drug interactions: Strong CYP3A inhibitors (for example, certain antifungals or antibiotics) or inducers (certain anticonvulsants or antimicrobial agents) can significantly alter lorlatinib exposure and safety. See CYP3A4 for a broader discussion of how these interactions affect many targeted therapies.
Special populations: In pregnancy, safety has not been established; use during pregnancy is generally discouraged. The safety and dosing considerations in patients with hepatic or renal impairment follow regulatory labeling and clinical guidelines discussed in physician references and manufacturer materials.
Activity beyond ALK: Lorlatinib has activity against ROS1 in preclinical and some clinical contexts, but its approved clinical use remains centered on ALK-positive disease. See ROS1 for the broader family of targets and related therapies.
Efficacy and clinical evidence
Key trials: The pivotal trials for lorlatinib focused on patients whose disease had progressed on or after prior ALK inhibitors. Results consistently showed meaningful activity in this setting, including radiographic responses and disease control, along with a tendency toward intracranial responses given lorlatinib’s CNS penetration. The drug has also been explored in first-line settings, with the aim of improving progression-free survival and delaying CNS progression compared with crizotinib in ALK-positive NSCLC.
Comparative context: In the landscape of ALK inhibitors, lorlatinib is positioned as a later-generation option designed to overcome common resistance mutations and to address brain metastases. Other ALK inhibitors in the class include crizotinib, alectinib, and brigatinib, each with its own profile of activity and CNS efficacy. See these related agents for context on sequencing and resistance patterns in ALK-rearranged disease.
Safety, tolerability, and monitoring
Common adverse effects: Hyperlipidemia (elevated cholesterol and triglycerides) is a frequent laboratory abnormality; edema, peripheral neuropathy, weight gain, and cognitive or mood changes are also observed in some patients. Hepatic transaminase elevations, rash, and anemia may occur, requiring regular monitoring of liver function tests and blood counts.
Serious risks: Interstitial lung disease/pneumonitis, although uncommon, is a potential serious adverse event with some ALK inhibitors and requires prompt evaluation if respiratory symptoms develop. Patients may also experience mood changes, sleep disturbances, or cognitive effects that warrant clinical attention and, if needed, dose modification.
Monitoring plan: Lipids, liver enzymes, hematologic parameters, and clinical assessments for CNS effects are typically part of routine safety monitoring. Dose adjustments or interruptions may be necessary to manage toxicity.
Pharmacology and pharmacokinetics
Absorption and distribution: Lorlatinib is administered orally and achieves substantial exposure in the CNS, aligning with its goal of controlling brain metastases.
Metabolism and elimination: It is predominantly metabolized by the hepatic enzyme system CYP3A4 and is cleared through hepatic pathways. This metabolic profile underpins the importance of avoiding or adjusting concomitant drugs that strongly affect CYP3A activity.
Pharmacokinetic considerations: Food does not have a major effect on lorlatinib exposure, but patient factors and co-administered medications can influence levels. Clinicians reference the official labeling and pharmacology resources for precise dosing guidance, including management of drug interactions.
Controversies and policy discussions
Cost and access: Like many targeted cancer therapies, lorlatinib carries a high price tag, which can affect patient access and payer coverage. Debates in health policy circles center on value-based pricing, negotiation strategies for major therapies, and the balance between incentivizing innovation and ensuring affordable treatment options for patients.
Sequencing and real-world use: As multiple ALK inhibitors accumulate in clinical practice, questions arise about the optimal sequencing of these agents to maximize clinical benefit, CNS control, and duration of response. Clinicians and health systems weigh trial data, biomarker-guided strategies, and patient preferences in decision-making. See precision medicine for broader discussions of how biomarker-driven therapy informs treatment choices.
Safety monitoring and value: Given the potential for CNS effects and metabolic disturbances, some observers emphasize the need for robust monitoring programs and patient education as part of value-based care, ensuring that benefits justify risks and costs over the course of treatment.