Lorlatinib is a selective tyrosine kinase receptor inhibitor used in the therapy of selected cases of advanced non-small cell lung cancer. Lorlatinib is associated with transient elevations in serum aminotransferase levels during treatment but has not been linked to instances of clinically apparent acute liver injury that have been described with other similar kinase inhibitors.
Lorlatinib (lor la' ti nib) is an orally available, small molecule inhibitor of the tyrosine kinase receptor of mutated anaplastic lymphoma kinase (ALK), which is the result of a chromosomal translocation found in about 5% of lung cancers. Patients with non-small cell lung cancer with the ALK mutation often respond to ALK inhibitor therapy with shrinkage of the tumor and apparent improvement in survival. However, resistance develops frequently as a result of further mutations in the cancer cells. Lorlatinib is a third generation ALK inhibitor that has activity against many of the known ALK resistance mutants. Lorlatinib received accelerated approval for use in the United States in 2018 for the treatment of refractory, advanced non-small cell lung cancer with the ALK translocation (a test for this genetic rearrangement was also approved). Lorlatinib is available in tablets of 25 and 100 mg under the brand name Lorbrena. The recommended dose is 100 mg by mouth once daily, with dose modification based upon tolerance. Side effects are common and include diarrhea, nausea, vomiting, anorexia, fatigue, diarrhea, visual disturbances, peripheral neuropathy, cognitive effects, dyspnea, weight gain, hyperlipidemia and edema. Uncommon, but potentially serious side effects include interstitial lung disease, atrial-ventricular block, QTc interval prolongation, cardiac arrhythmias and fetal-embryonal toxicity.
In large early clinical trials, elevations in serum aminotransferase levels occurred in up to 28% of patients treated with standard doses of lorlatinib but were above 5 times ULN in only 2% of patients and rarely led to early discontinuation of therapy. The abnormalities were typically transient, asymptomatic and not associated with jaundice. In prelicensure clinical trials there were no instances of clinically apparent liver injury. In contrast, most other ALK inhibitors have been linked to instances of acute liver injury which can be severe and even fatal. The liver injury typically arises within 4 to 12 weeks of starting therapy and presents with marked elevations in serum aminotransferase levels followed by jaundice and progressive hepatic dysfunction. While lorlatinib has not been associated with instances of severe liver injury, it has had limited clinical use.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism by which lorlatinib might cause liver injury is unknown. Lorlatinib is metabolized in the liver largely via CYP 3A4, and liver injury may be due to accumulation of a toxic or immunogenic intermediate. Lorlatinib is susceptible to drug-drug interactions, and drugs that are strong inhibitors or inducers of CYP 3A should be avoided during its use.
Outcome and Management
Routine monitoring of liver tests is recommended for patients starting lorlatinib and at intervals thereafter. Serum aminotransferase elevations above 5 times the upper limit of normal should lead to dose interruption. If changes persist, are severe, or reoccur on restarting, lorlatinib should be discontinued. Persons who develop liver injury using therapy with a specific ALK inhibitor can often be treated with other ALK inhibitors without recurrence of liver injury, but should be monitored carefully during treatment after hepatotoxicity from a related agent.
REPRESENTATIVE TRADE NAMES
Lorlatinib – Lorbrena®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 15 April 2019
Abbreviations used: NSCLC, non-small cell lung cancer; ALK, anaplastic lymphoma kinase.
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