Clinical Pharmacology Corner: FDA Approves LORBRENA (Lorlatinib)

FDA Approves LORBRENA (Lorlatinib) for Anaplastic Lymphoma Kinase-Positive Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on Certain Other Kinase Inhibitors

On November 2, 2018, the U.S. Food and Drug Administration (FDA) approved LORBRENA (lorlatinib) for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on:

• crizotinib and at least one other ALK inhibitor for metastatic disease; or 
• alectinib as the first ALK inhibitor therapy for metastatic disease; or 
• ceritinib as the first ALK inhibitor therapy for metastatic disease.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 

The approved recommended dosage of LORBRENA is 100 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Monitor serum cholesterol and triglycerides before initiating LORBRENA, 1 and 2 months after initiating LORBRENA, and periodically thereafter. Monitor ECG prior to initiating LORBRENA and periodically thereafter.

LORBRENA is contraindicated with concomitant use of strong CYP3A inducers, due to the potential for serious hepatotoxicity. A broad spectrum of central nervous system effects (i.e., seizures, hallucinations, and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep), hyperlipidemia, atrioventricular block, and interstitial lung disease/pneumonitis can occur in patients receiving LORBRENA that may require discontinuation or dosage modification based on severity.  Advise pregnant women of the potential risk to a fetus. Advise patients and partners of reproductive potential to use effective methods of contraception during treatment with LORBRENA and several months after the final dose. Additional information regarding recommended dosage modifications, warnings, and precautions can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) 

• MOA: Lorlatinib is a kinase inhibitor with in vitro activity against ALK.
• General PK: Lorlatinib C_max increases proportionally, and AUC increases slightly less than proportional at 0.1 to 2 times the approved recommended dosage.
• Absorption: Lorlatinib absolute bioavailability is 81%. The median (min-max) lorlatinib T_maxincreases from 1.2 hours (0.5 to 4 hours) following a single dose to 2 hours (0.5 to 23 hours) at steady state. 
• Distribution: Protein binding of lorlatinib is 66% in vitro. The steady state volume of distribution is 305 L following intravenous administration.
• Elimination: The mean plasma half-life of lorlatinib is 24 hours. Lorlatinib clearance increases from 11 L/h following a single dose to 18 L/h at steady state, indicating autoinduction. 
• Metabolism: Lorlatinib is primarily metabolized by CYP3A4 and UGT1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3 in vitro. 
• Excretion: Following a single radiolabeled dose, 48% of the radioactivity was recovered in urine (< 1% as unchanged) and 41% in feces (about 9% as unchanged). 
• PD: Exposure-response relationships for grade 3 or 4 adverse reactions, including hypercholesterolemia, were observed at steady-state exposures at the approved recommended dosage, and the probability of occurrence of adverse reactions increases with increasing lorlatinib exposure.  
• Cardiac Electrophysiology: At the approved recommended dosage, LORBRENA prolonged the PR interval in a concentration-dependent manner, and the maximum mean change from baseline was 16.4 ms. The PR interval was prolonged in 14% of patients with a PR interval < 200 ms at baseline. Atrioventricular block occurred in 1% of patients. LORBRENA did not result in any large mean increases in the QTcF interval (i.e., > 20 ms).

Drug Interactions

• Strong or Moderate CYP3A Inducers: LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA. Avoid concomitant use of LORBRENA with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers is unavoidable, monitor ALT, AST, and bilirubin as recommended. 
• Strong CYP3A Inhibitors: Avoid concomitant use of LORBRENA with strong CYP3A inhibitors. If concomitant use is unavoidable, reduce the LORBRENA dosage per the full prescribing information linked below.  
• CYP3A Substrates: Avoid concomitant use of LORBRENA with CYP3A substrates where minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.

Use in Specific Populations

No clinically meaningful differences in lorlatinib pharmacokinetics were observed based on age (19 to 85 years), sex, race/ethnicity, body weight, mild to moderate renal impairment (CLcr 30 to 89 mL/min), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1.5 × ULN and any AST), or metabolizer phenotypes for CYP3A5 and CYP2C19. The effect of moderate to severe hepatic impairment or severe renal impairment on lorlatinib pharmacokinetics is unknown. 

Efficacy and Safety

Efficacy of LORBRENA was demonstrated in a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter study in a subgroup of patients with ALK-positive metastatic NSCLC previously treated with one or more ALK kinase inhibitors. Major efficacy outcome measures were overall response rate (ORR) and intracranial ORR. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.

Most common adverse reactions (incidence ≥ 20%) are edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea.

Full prescribing information is available at https://go.usa.gov/xPpKE. 

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.