What is lorlatinib?
Lorlatinib is a third-generation tyrosine kinase inhibitor towards anaplastic lymphoma kinase (ALK) and ROS1 in non-small cell lung cancer (NSCLC). Unique characteristics of this agent include its highly selective activity towards known ALK resistance mechanisms, as well as an ability to penetrate the blood brain barrier.
Lorlatinib reversibly binds to the tyrosine kinase receptor. It has been found to have activity against mutations found following disease progression that follows prior ALK inhibitors. Lorlatinib has dose-dependent inhibition of ALK phosphorylation.
What is this approved for?
Lorlatinib was granted accelerated approval for patients with ALK-positive, metastatic NSCLC who are found to have progressed on crizotinib and one additional ALK inhibitor or progressed on ceritinib or alectinib as the first ALK inhibitor.
Lorlatinib was approved based on the results of a subgroup of patients with ALK-positive metastatic NSCLC who previously received one or more ALK inhibitors. A total of 215 patients enrolled in a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter study (Study B7461001). Patients with asymptomatic CNS metastases were eligible and 89 patients met this criteria. Patients received lorlatinib 100 mg orally once daily. Overall response rate (ORR) and intracranial ORR were the major efficacy endpoints that were assessed by independent central review committee. Additional endpoints of interest included duration of response (DOR) and intracranial DOR.
ORR was 48 percent (95% CI: 42, 55) with 4 percent having a complete response and 44 percent a partial response. Intracranial ORR was 60 percent (95% CI: 49, 70) with 21 percent complete response and 38 percent partial response. DOR was 12.5 months (95% CI: 8.4, 23.7) and intracranial DOR was 19.5 months (95% CI: 12.4, NR).
How do you administer this drug?
Lorlatinib is given as a 100 mg oral tablet taken daily. It can be given with or without food.
Are there any premedications needed for lorlatinib?
There are no required premedications for lorlatinib.
What are the common side effects associated with lorlatinib (> or =10%)?
Hematologic: anemia, thrombocytopenia, lymphocytopenia
* Cardiovascular: edema
* Central nervous system: peripheral neuropathy, cognitive dysfunction, mood disorder, speech disturbance, sleep disorder, headache
* GI: diarrhea, increased serum lipase, nausea
* General: fatigue
* Dermatologic: skin rash
* Endocrine & Metabolic: hypercholesterolemia, hypertriglyceridemia, hyperglycemia, weight gain
* Neuromuscular & Skeletal: myalgia, arthralgia
* Hepatic: increased AST/ALT/alkaline phosphatase
* Respiratory: Dyspnea
What are the uncommon side effects associated with lorlatinib (less than 10%)?
Additional side effects include atrioventricular block (1%), hallucination (7%), seizure (3%), mental status changes (2%), and interstitial pulmonary disease/pneumonitis (~2%).
Are there any important drug interactions?
Lorlatinib is a major substrate of CYP3A4. Lorlatinib use is contraindicated with strong CYP3A inducers. Avoid use with moderate CYP3A inducers, strong CYP3A inhibitors, and substrates of CYP3A with a narrow therapeutics index.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no known renal or hepatic dose adjustments for lorlatinib; however, it has not been studied in severe renal or hepatic dysfunction.
Practical tips
* If a patient is started on new medications, it is recommended to evaluate for drug-drug interactions as lorlatinib has significant drug interactions. Ensure three half-lives have passed prior to initiating lorlatinib following discontinuation of strong CYP3A inducers.
* Hepatotoxicty has developed with concomitant lorlatinib use and moderate CYP3A inducers. Monitor AST, ALT, and bilirubin 48 hours after initiating lorlatinib in patients who are unable to discontinue moderate CYP3A inducers followed by at least three times during the first week of lorlatinib initiation.
* If a dose reduction is needed for lorlatinib, it should be done in 25 mg increments.
What should my patients know about lorlatinib?
Patients should contact their health care provider if they experience any of the following:
* Shortness of breath
* New or worsening cardiac symptoms
* Changes in mood, confusion, or anxiety
What else should I know about lorlatinib?
* Monitor cholesterol and triglycerides at initiation, monthly for the first 2 months, and periodically thereafter. Initiation of lipid-lowering agents can be required.
* Monitor for seizures, sleep disturbances, mood changes, and speech effects while on therapy. The median onset to initial onset of any CNS effect was 1.2 months with ranges in severity.
What useful links are available?
* https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm625027.htm
* https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf
Any ongoing clinical trials related to lorlatinib?
Clinical trials with lorlatinib are being conducted to investigate the place in therapy for the treatment of ALK-positive NSCLC. Additional trials are reviewing the role of lorlatinib in ROS1 rearranged metastatic NSCLC, ALK-positive lymphoma, and in combination with immunotherapy for ALK-positive NSCLC. More information is available about the clinical trials at https://clinicaltrials.gov.
JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.