Lorlatinib Oral

Non-small Cell Lung Cancer

Lorlatinib is used for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC).^[1] The drug has been designated an orphan drug by the FDA for the treatment of ALK-positive or c-ros oncogene-1 (ROS-1)-positive NSCLC.^[7]

Efficacy and safety of lorlatinib in the treatment of ALK-positive NSCLC is supported by several randomized controlled trials.^[2][48] Lorlatinib has demonstrated substantial overall and intracranial activity in treatment-naive and previously treated patients with ALK-positive NSCLC.^[2] Guidelines generally support the use of lorlatinib in the second- or third-line setting in patients with NSCLC previously treated with an ALK inhibitor in the first-line setting.^[35]

The efficacy of lorlatinib in treatment-naive patients with NSCLC harboring an ALK rearrangement was evaluated in an open-label, randomized, active-controlled trial (CROWN study).^[1][48] The primary end point was progression-free survival.^[48] In this study, 296 patients were randomized to receive lorlatinib 100 mg orally once daily or crizotinib 250 mg orally twice daily.^[48] The median age of patients enrolled in the study was 59 years; 35% of patients were 65 years or older, 59% were female, 49% were white, 44% were Asian, and 0.3% were Black.^[1] The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 or 1 in 96% of patients.^[1] The majority of patients had adenocarcinoma (95%) and had never smoked (59%).^[1] CNS metastases were present in 26% of patients: 30 of these patients had measurable CNS lesions.^[1] The median duration of follow-up was 18.3 and 14.8 months in patients receiving lorlatinib and crizotinib, respectively.^[48] At the time of data analysis, median progression-free survival had not been reached in patients receiving lorlatinib; however, the risk of disease progression or death was reduced by 72% in patients receiving lorlatinib compared with those receiving crizotinib (hazard ratio: 0.28; 95% confidence interval 0.19-0.41).^[1] Objective response and intracranial response rate also was substantially improved in patients who received lorlatinib compared with those who received crizotinib.^[48] The overall response rate was 76% in patients who received lorlatinib and 58% in those who received crizotinib.^[1] The median duration of response had not been reached in patients receiving lorlatinib and was 11 months in patients receiving crizotinib; response duration of >=6, >=12, and >=18 months was 89, 70, and 30% in patients receiving lorlatinib, respectively, and 62, 27, and 11% in patients receiving crizotinib, respectively.^[1] Among patients with measurable CNS metastases at baseline, complete intracranial response was observed in 71 and 8% of patients who received lorlatinib and crizotinib, respectively.^[1][48]

The efficacy of lorlatinib in patients previously treated with an ALK inhibitor is based on the results of a subgroup of 215 patients enrolled in a multicenter, nonrandomized, open-label, dose-ranging, phase 2 study (Study B7461001).^[1] Prior therapy included crizotinib or 1-3 non-crizotinib ALK inhibitors, all with or without chemotherapy.^[1][2] Patients received lorlatinib 100 mg orally once daily until disease progression, unacceptable toxicity, death, or study withdrawal occurred.^[1][2] The primary efficacy end points were overall response rate and intracranial overall response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as evaluated by a central independent review committee (IRC); additional outcome measures included duration of response and intracranial duration of response.^[1][2] The median age of patients included in the study analysis was 53 years (range: 29-85 years), 51% of patients were white and 34% were Asian, and 59% were female.^[1] All patients had metastatic disease and 95% had adenocarcinoma histology.^[1] Approximately 30% of patients evaluated had disease progression during crizotinib therapy, and 13, 35, or 22% had disease progression during prior therapy with 1 (non-crizotinib), 2, or 3 ALK inhibitors, respectively.^[1] CNS metastases were present in 69% of patients and 60% of such patients had previously received radiation to the brain.^[1] The IRC-assessed overall response rate with lorlatinib was 48%; partial responses were achieved in 44% of patients and 4% had a complete response.^[1] The median duration of response was 12.5 months.^[1] In the subgroup of 89 patients with measurable brain metastases at baseline, the IRC-assessed intracranial overall response rate was 60% (38% partial responses and 21% complete responses) and the median duration of intracranial response was 19.5 months.^[1]

Clinical Perspective

A relatively small subset of patients with NSCLC (approximately 3-7%) have ALK-positive disease, which indicates potential responsiveness to ALK inhibitor therapy (e.g., alectinib, brigatinib, ceritinib, crizotinib).^{[2][8][9][10]} Patients with this form of lung cancer typically are nonsmokers or have a history of light smoking, and are younger in age and often have adenocarcinoma histology.^{[6][8][9][10][11]} Although crizotinib is highly active in patients with ALK-positive NSCLC, most patients treated with the drug eventually experience disease progression, limiting the drug's long-term therapeutic potential.^{[2][8][9][11]} Disease progression in patients receiving ALK inhibitors (e.g., alectinib, ceritinib, crizotinib) can result from acquired resistance mutations in ALK, amplification of gene expression, activation of alternate signaling pathways, and/or progression of brain metastases (e.g., because of poor distribution of crizotinib into the CSF).^{[2][3][8][9][11]}

The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations such as ALK mutations.^[35] ASCO/OH state that alectinib or brigatinib should be offered in the first-line setting in patients with stage IV NSCLC and driver alterations in ALK; however, if alectinib or brigatinib are not available, ceritinib or crizotinib should be offered in the first-line setting.^[35] In patients with a performance status of 0-2 who received prior therapy with alectinib or brigatinib in the first-line setting, lorlatinib may be offered in the second-line setting.^[35] In patients with a performance status of 0-2 who received prior therapy with crizotinib in the first-line setting, and alectinib, brigatinib, or ceritinib in the second line-setting, lorlatinib may be offered in the third-line setting.^[35]

ASCO/OH state that in patients with previously untreated NSCLC harboring driver alterations in ROS-1 who have a performance status of 0-2, ceritinib or lorlatinib may be offered.^[35]

General

Pretreatment Screening

Confirm presence of ALK-positivity in tumor specimens in patients with metastatic NSCLC.^[1]Verify pregnancy status in females of reproductive potential prior to initiating therapy.^[1]Assess serum cholesterol and triglyceride concentrations prior to initiating therapy; initiate or optimize antilipemic therapy as clinically indicated.^[1]Perform ECG prior to initiating therapy.^[1]Assess blood pressure prior to initiating therapy; blood pressure must be controlled prior to initiation of the drug.^[1]Assess fasting serum glucose concentrations prior to initiation of the drug.^[1]Assess concomitant therapy, including prescription drug, OTC drugs, and dietary or herbal supplements.^[1] Concomitant use of lorlatinib with potent inducers of CYP3A is contraindicated

Patient Monitoring

Monitor blood pressure after 2 weeks of therapy and then at least monthly during therapy.^[1]Monitor serum cholesterol and triglyceride concentrations 1 and 2 months after initiating therapy, and then periodically thereafter.^[1] Initiate or optimize antilipemic therapy as clinically indicated.^[1]Monitor ECG periodically during therapy.^[1]Monitor fasting serum glucose concentration periodically during therapy.^[1]

Administration

Lorlatinib is administered orally once daily at the same time each day without regard to food.^[1] The tablets should be swallowed whole and should not be crushed, chewed, or split.^[1] The manufacturer states that lorlatinib tablets should not be taken if they are broken, cracked, or otherwise not intact.^[1]

If a dose of lorlatinib is missed, the dose should be taken as soon as it is remembered unless the next dose is due within 4 hours.^[1] Two doses should not be taken at the same time to make up for a missed dose.^[1] If vomiting occurs after taking a dose, the next dose should be taken at the regularly scheduled time; an additional dose should not be taken.^[1]

Dosage

Non-small Cell Lung Cancer

For the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), the recommended adult dosage of lorlatinib is 100 mg once daily.^[1] Therapy with the drug should be continued until disease progression or unacceptable toxicity occurs.^[1]

Dosage Modification for Toxicity

Dosing interruption and/or dosage reduction of lorlatinib may be necessary based on individual safety and tolerability.^[1]

In the CROWN study, dosage reduction because of adverse reactions was necessary in approximately 21% of patients treated with lorlatinib (most commonly for edema, hypertriglyceridemia, and peripheral neuropathy).^[1] Among previously-treated patients with ALK-positive NSCLC, approximately 48% required dosage interruption and 24% of patients required at least one dosage reduction, most commonly for edema, peripheral neuropathy, cognitive effects, and mood effects.^[1][2] Treatment interruption due to adverse effects was required in 49% of patients, most commonly for hypertriglyceridemia, edema, pneumonia, cognitive effects, mood effects, or hypercholesterolemia.^[1]

If dosage reduction is necessary, an initial dosage reduction to 75 mg once daily is recommended.^[1] If further dosage reduction is necessary, the dosage should be reduced to 50 mg once daily.^[1] If a dosage of 50 mg once daily is not tolerated, lorlatinib should be permanently discontinued.^[1]

CNS Effects

If grade 1 adverse CNS effects occur, lorlatinib therapy may be continued at the same dosage or therapy may be interrupted until recovery to baseline.^[1] Therapy may then be resumed at the same dosage or at the next lower dosage.^[1]

If grade 2 or 3 adverse CNS effects occur, lorlatinib therapy should be interrupted until recovery to grade 0 or 1.^[1] Therapy may then be resumed at the next lower dosage.^[1]

If grade 4 adverse CNS effects occur, lorlatinib therapy should be permanently discontinued.^[1]

Hyperlipidemia

If grade 4 hypercholesterolemia (serum cholesterol concentration exceeding 500 mg/dL) and/or grade 4 hypertriglyceridemia (serum triglyceride concentration exceeding 1000 mg/dL) occurs, lorlatinib therapy should be interrupted and appropriate antilipemic therapy should be initiated, the dosage of existing antilipemic therapy should be increased, or the existing antilipemic regimen should be changed to a new lipid-lowering therapy.^[1][14] Lorlatinib therapy may be resumed at the same dosage upon recovery of hypercholesterolemia and/or hypertriglyceridemia to grade 2 or less.^[1]

If severe hypercholesterolemia and/or hypertriglyceridemia recurs despite optimal antilipemic therapy, therapy should then be resumed at the next lower dosage of lorlatinib.^[1][14]

Atrioventricular Block

If second-degree atrioventricular (AV) block occurs, lorlatinib therapy should be interrupted until the PR interval is less than 200 msec.^[1] Lorlatinib should then be resumed at the next lower dosage.^[1]

If complete AV block occurs, lorlatinib therapy should be interrupted until a pacemaker is placed or the PR interval is less than 200 msec.^[1] If a pacemaker is placed, lorlatinib therapy may be resumed at the same dosage.^[1] If a pacemaker is not placed, lorlatinib therapy should be resumed at the next lower dosage.^[1]

If complete AV block recurs, a pacemaker should be placed or lorlatinib therapy should be permanently discontinued.^[1]

Interstitial Lung Disease/Pneumonitis

If treatment-related interstitial lung disease/pneumonitis of any grade occurs, lorlatinib therapy should be permanently discontinued.^[1]

Hypertension

If grade 3 hypertension (defined as systolic blood pressure [SBP] >=160 mm Hg, diastolic blood pressure [DBP] >=100 mm Hg, or elevation requiring medical intervention, more than one antihypertensive drug, or more intensive therapy than previously indicated) occurs, withhold lorlatinib therapy; when hypertension improves to grade 1 or less (SBP <140 mm Hg and DBP <90 mm Hg), may then resume lorlatinib at the same dosage.^[1] If grade 3 hypertension recurs, withhold lorlatinib therapy until hypertension improves to grade 1 or less, and then resume lorlatinib at a reduced dosage.^[1] If adequate control of hypertension cannot be achieved with optimal medical management, lorlatinib should be permanently discontinued.^[1]

If grade 4 (life-threatening or requires urgent intervention) hypertension occurs, withhold lorlatinib; when hypertension improves to grade 1 or less, may then resume lorlatinib at a reduced dosage or permanently discontinue drug.^[1] If grade 4 hypertension recurs, permanently discontinue lorlatinib.^[1]

Hyperglycemia

If grade 3 hyperglycemia (serum glucose concentration >250 mg/dL) occurs despite optimal antihyperglycemic therapy or if grade 4 hyperglycemia occurs, withhold lorlatinib until adequate glycemic control is achieved; may then resume lorlatinib at the next lower dosage.^[1] Lorlatinib should be permanently discontinued if glycemic control cannot be achieved.^[1]

Other Toxicity

If any other grade 1 or 2 adverse reaction occurs, lorlatinib therapy may be continued at the same dosage or reduced to the next lower dosage.^[1]

If any other grade 3 or 4 adverse reaction occurs, lorlatinib therapy should be interrupted until recovery to grade 2 or less, or to baseline.^[1] Lorlatinib therapy may then be resumed at the next lower dosage.^[1]

Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of lorlatinib with potent inducers of cytochrome P-450 (CYP) isoenzyme 3A is contraindicated.^[1] Potent CYP3A inducers should be discontinued for 3 plasma half-lives of the potent CYP3A inducer prior to initiating lorlatinib therapy.^[1]

Concomitant use of lorlatinib with moderate inducers of CYP3A should be avoided.^[1] If concomitant use of a moderate CYP3A inducer cannot be avoided, increase lorlatinib dosage to 125 mg once daily.^[1]

Concomitant use of lorlatinib with potent inhibitors of CYP3A should be avoided.^[1] If concomitant use of a potent CYP3A inhibitor cannot be avoided, the initial dosage of lorlatinib should be reduced from 100 mg once daily to 75 mg once daily.^[1] In patients who have had a dosage reduction to 75 mg once daily because of adverse reactions, the dosage of lorlatinib should be reduced to 50 mg once daily during concomitant use of a potent CYP3A inhibitor.^[1] If concomitant use of the potent CYP3A inhibitor is discontinued, the lorlatinib dosage should be increased (after 3 plasma half-lives of the CYP3A inhibitor) back to the dosage that was used prior to initiation of the potent CYP3A inhibitor.^[1]

Concomitant use of lorlatinib with fluconazole should be avoided.^[1] If concomitant use with fluconazole cannot be avoided, the initial dosage of lorlatinib should be reduced from 100 mg once daily to 75 mg once daily.^[1]

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment (total bilirubin concentrations not exceeding the upper limit of normal [ULN] with AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding 1 but not exceeding 1.5 times the ULN with any AST concentration).^[1]

The recommended dosage of lorlatinib has not been established in patients with moderate or severe hepatic impairment.^[1]

Renal Impairment

In patients with severe renal impairment (creatinine clearance 15 to <30 mL/minute), the dosage of lorlatinib should be reduced from 100 mg to 75 mg once daily.^[1]

No dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).^[1]

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.^[1]

Contraindications

Lorlatinib is contraindicated in patients receiving potent cytochrome P-450 (CYP) isoenzyme 3A inducers because of the potential for serious hepatotoxicity.^[1]

Warnings/Precautions

Serious Hepatotoxicity with Concurrent Use of Potent CYP3A Inducers

Severe hepatotoxicity occurred in 10 of 12 healthy individuals receiving a single dose of lorlatinib with multiple daily doses of rifampin (a potent CYP3A inducer) during a drug interaction study.^[1] Grade 3 or 4 elevations in ALT or AST concentrations occurred in 83% and grade 2 elevations occurred in 8% of individuals who received the drugs concomitantly during the study.^[1] ALT or AST elevations occurred within 3 days of concomitant administration and returned to within normal limits after a median of 15 days (range: 7-34 days).^[1] The median time to recovery was 18 days following grade 3 or 4 elevations in ALT or AST concentrations and 7 days following grade 2 elevations.^[1] Concomitant use of lorlatinib with drugs that are potent CYP3A inducers is contraindicated.^[1] Potent CYP3A inducers should be discontinued for 3 plasma half-lives of the potent CYP3A inducer prior to initiating lorlatinib therapy.^[1]

Concomitant use of lorlatinib with drugs that are moderate CYP3A inducers should be avoided.^[1]

CNS Effects

Lorlatinib can cause a wide variety of adverse CNS effects, including seizures, psychotic effects, and changes in cognitive function (including memory impairment, cognitive disorder, and amnesia), mood (including suicidal ideation/suicidality, irritability, anxiety, depression, and labile affect), speech, mental status, and sleep.^[1][2][14] Although adverse CNS effects associated with lorlatinib therapy generally are mild in severity and intermittent and improve or resolve upon dosage modification,^[14] treatment interruption, dosage reduction, or drug discontinuance may be required depending on their severity.^[1]

In clinical trials, CNS effects occurred in 52% of 476 patients who received lorlatinib 100 mg once daily.^[1] Cognitive, mood, speech, sleep, and psychotic effects were observed in 28, 21, 11, 12, and 7% of patients, respectively.^[1] Grade 3 or 4 cognitive, mood, speech, and psychotic effects were reported in 2.9, 1.7, 0.6, and 0.6% of patients, respectively.^[1] Mental status changes occurred in 1.3% of patients; 1.1% of these events were grade 3 or 4 in severity.^[1] Seizures occurred in 1.9% of patients, sometimes in conjunction with other neurologic findings.^[1] The median time to onset of any CNS effect was 1.4 months (range 1 day to 3.4 years).^[1]

Hyperlipidemia

Increases in serum cholesterol and triglyceride concentrations may occur in patients receiving lorlatinib.^[1][2][14] Hypercholesterolemia or hypertriglyceridemia occurred in 90% or more of patients receiving the recommended dosage of lorlatinib in Study B7461001 and the CROWN study; 83% of patients receiving lorlatinib required initiation of antilipemic therapy.^[1] Grade 3 or 4 elevations in serum total cholesterol or triglyceride concentrations occurred in 18 or 19% of patients treated with lorlatinib, respectively.^[1] Treatment interruption or dosage reduction of lorlatinib was required in approximately 7 or 3% of patients, respectively, due to hypercholesterolemia or hypertriglyceridemia.^[1] The median time to onset of hypercholesterolemia or hypertriglyceridemia was 15 days; the median time to initiation of antilipemic therapy was 17 days.^[1]

Serum cholesterol and triglycerides should be assessed prior to initiating lorlatinib therapy, 1 and 2 months after initiating therapy, and periodically thereafter.^[1] Antilipemic therapy should be initiated or the dosage of existing antilipemic therapy should be increased in patients with hyperlipidemia.^[1][14] Temporary interruption followed by resumption of lorlatinib therapy at the same dosage or at a reduced dosage may be necessary, depending on the severity of the hyperlipidemia.^[1][14]

Atrioventricular Block

PR-interval prolongation and atrioventricular (AV) block may occur in patients receiving lorlatinib.^[1] AV block has been reported in 1.9% of 476 patients who received lorlatinib at the recommended dosage who had a baseline ECG; 0.2% of these patients experienced grade 3 AV block and underwent pacemaker placement.^[1] ECG monitoring is recommended prior to initiating lorlatinib and periodically during therapy.^[1] If AV block occurs, lorlatinib therapy should be interrupted; dosage reduction may be necessary unless a pacemaker is placed.^[1] If complete AV block recurs in patients without a pacemaker, lorlatinib should be permanently discontinued.^[1]

Interstitial Lung Disease/Pneumonitis

Severe or life-threatening adverse pulmonary reactions consistent with interstitial lung disease (ILD)/pneumonitis may occur in patients receiving lorlatinib.^[1] ILD or pneumonitis has been reported in 1.9% of patients receiving lorlatinib 100 mg once daily, including grade 3 or 4 ILD or pneumonitis in 0.6% of patients.^[1] One patient (0.3%) discontinued the drug because of ILD/pneumonitis.^[1]

Patients receiving lorlatinib who present with worsening of respiratory symptoms indicative of ILD or pneumonitis (e.g., dyspnea, cough, fever) should be promptly evaluated.^[1] Lorlatinib therapy should be immediately interrupted in patients with suspected ILD/pneumonitis.^[1] The drug should be permanently discontinued in patients with treatment-related ILD or pneumonitis of any severity.^[1]

Hypertension

Hypertension has occurred in 13% of patients who received lorlatinib.^[1] Grade 3 or 4 hypertension has been reported in 6% of patients.^[1] The median time to onset of hypertension was 6.4 months.^[1] Temporary interruption of lorlatinib therapy was necessary in 2.3% of patients experiencing hypertension.^[1]

Blood pressure should be monitored after 2 weeks of treatment and at least monthly thereafter.^[1] Blood pressure must be controlled prior to initiation of lorlatinib therapy.^[1]

Hyperglycemia

Hyperglycemia has occurred in 9% of patients who received lorlatinib.^[1] Grade 3 or 4 hyperglycemia has been reported in 3.2% of patients.^[1] The median time to onset of hyperglycemia was 4.8 months.^[1] Temporary interruption of lorlatinib therapy was necessary in 0.8% of patients experiencing hyperglycemia.^[1]

Fasting serum glucose should be assessed prior to initiation of lorlatinib and periodically thereafter.^[1] If hyperglycemia occurs, temporary interruption of therapy, dosage reduction, or permanent discontinuance of therapy may be necessary based on severity of hyperglycemia.^[1]

Fetal/Neonatal Morbidity and Mortality

Lorlatinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.^[1] There are no clinical data on the use of lorlatinib in pregnant women.^[1] Malformations, increased post-implantation loss, and abortion were observed when the drug was administered to pregnant animals during the period of organogenesis at maternal exposures that were equal to or less than human exposure at the recommended dosage of 100 mg once daily based on area under the concentration-time curve (AUC).^[1]

Pregnancy should be avoided during lorlatinib therapy.^[1] The manufacturer recommends confirmation of pregnancy status prior to initiation of lorlatinib in females of reproductive potential; such females should use effective nonhormonal contraception during lorlatinib therapy and for at least 6 months after the drug is discontinued.^[1] In addition, males with female partners of reproductive potential should use effective methods of contraception while receiving lorlatinib and for at least 3 months after the drug is discontinued.^[1] Pregnant females and females of reproductive potential should be apprised of the potential fetal hazard.^[1]

Specific Populations

Pregnancy

Although there are no clinical data in pregnant females to date, animal studies and its mechanism of action suggest that lorlatinib may cause fetal harm.^[1]

Lactation

It is not known whether lorlatinib or its metabolites are distributed into either human or animal milk or if the drug has any effect on milk production or the nursing infant.^[1] Because of the potential for adverse reactions to lorlatinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 7 days after the drug is discontinued.^[1]

Females and Males of Reproductive Potential

Based on findings in male reproductive organs in animal studies, lorlatinib may transiently impair male fertility.^[1]

Verify pregnancy status prior to initiation of lorlatinib in females of reproductive potential; such females should use effective nonhormonal contraception during lorlatinib therapy and for at least 6 months after the drug is discontinued.^[1]

Males with female partners of reproductive potential should use effective methods of contraception while receiving lorlatinib and for at least 3 months after the drug is discontinued.^[1] Pregnant females and females of reproductive potential should be apprised of the potential fetal hazard.^[1]

Pediatric Use

Safety and efficacy of lorlatinib have not been established in pediatric patients.^[1]

Geriatric Use

In Study B7461001 and the CROWN study evaluating lorlatinib in patients with NSCLC, approximately 18 and 40%, respectively, of patients receiving lorlatinib at the recommended dosage were 65 years of age or older.^[1] Although data are limited, no clinically important differences in safety or efficacy were observed between geriatric patients and younger adults in this study.^[1]

Age (19-85 years) does not appear to have clinically important effects on the pharmacokinetics of lorlatinib.^[1]

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentrations not exceeding the upper limit of normal [ULN] with AST concentrations exceeding the ULN, or total bilirubin concentrations exceeding 1 but not exceeding 1.5 times the ULN with any AST concentration) did not have clinically important effects on the pharmacokinetics of lorlatinib; dosage adjustment in patients with mild hepatic impairment is therefore not necessary.^[1]

Pharmacokinetics of lorlatinib have not been studied to date in patients with moderate or severe hepatic impairment.^[1]

Renal Impairment

Mild to moderate renal impairment (creatinine clearance of 30-89 mL/minute) did not have clinically important effects on the pharmacokinetics of lorlatinib; dosage adjustment in patients with mild or moderate renal impairment is therefore not necessary.^[1]

Dosage reduction is recommended in patients with creatinine clearance 15 to <30 mL/minute.^[1] In patients with creatinine clearance 15 to <30 mL/minute, systemic exposure of lorlatinib was increased by 42% compared with patients with normal renal function.^[1] Effects of end-stage renal disease or dialysis on the pharmacokinetics of lorlatinib are not known.^[1]

Common Adverse Effects

Adverse effects reported in >=20% of patients who received lorlatinib 100 mg once daily for the treatment non-small cell lung cancer (NSCLC) included edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, and cough.^[1] The most commonly reported grade 3 or 4 laboratory abnormalities (occurring in >=20% of patients) included hypercholesterolemia and hypertriglyceridemia.^[1]

Lorlatinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions by CYP isoenzymes 2C8, 2C19, and 3A5 and UGT1A3.^[1] In vitro studies indicate that lorlatinib inhibits P-glycoprotein (P-gp), organic cation transporter (OCT) 1, organic anion transporter (OAT) 3, multidrug and toxin extrusion (MATE) 1, and intestinal breast cancer resistance protein (BCRP).^[1]

In vitro studies indicate that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A and that it activates the pregnane X receptor (PXR); the net effect in vivo is induction.^[1] Lorlatinib induces CYP2B6 and activates the human constitutive androstane receptor (CAR).^[1] Lorlatinib and its major metabolite M8 do not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 nor UGT isoenzymes 1A1, 1A4, 1A6, 1A9, 2B7, or 2B15.^[1] M8 does not inhibit CYP3A nor induce CYP isoenzymes 1A2, 2B6, and CYP3A.^[1]

Lorlatinib does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OAT1, OCT2, MATE2K, and systemic BCRP.^[1] M8 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K.^[1]

Drugs Affecting Hepatic Microsomal Enzymes

Inducers of CYP3A

Concomitant use of lorlatinib with potent CYP3A inducers may result in severe hepatotoxicity.^[1] Grade 3 or 4 elevations in serum ALT or AST concentrations occurred in 83% and grade 2 elevations occurred in 8% of healthy individuals who received the potent CYP3A inducer rifampin (600 mg daily on days 1-8) and lorlatinib (single 100-mg dose on day 8) in a drug interaction study.^[1] Grade 2-4 elevations in hepatic enzymes (ALT or AST) occurred within 3 days of concomitant administration.^[1] In addition, peak plasma concentrations and area under the concentration-time curve (AUC) of lorlatinib were decreased by 76 and 85%, respectively.^[1] The mechanism of hepatotoxicity is thought to be through activation of the PXR by lorlatinib and rifampin, which are both PXR agonists.^[1]

Concomitant use of lorlatinib with potent CYP3A inducers is contraindicated.^[1] Potent CYP3A inducers must be discontinued and 3 plasma half-lives of the potent CYP3A inducer must elapse prior to initiation of lorlatinib therapy.^[1]

Concomitant use of lorlatinib with moderate CYP3A inducers may decrease serum concentrations of lorlatinib and reduced efficacy of the drug.^[1] Concomitant use of lorlatinib with drugs that are moderate CYP3A inducers should be avoided.^[1] If concomitant use of moderate CYP3A inducers cannot be avoided, the dosage of lorlatinib should be increased to 125 mg once daily.^[1]

Inhibitors of CYP3A

Concomitant use of lorlatinib with potent inhibitors of CYP3A may increase plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse effects.^[1] Concurrent administration of itraconazole (200 mg daily) and lorlatinib (single 100-mg dose) in healthy individuals increased peak plasma concentrations and AUC of lorlatinib by 24 and 42%, respectively.^[1][6]

Concomitant use of lorlatinib with potent CYP3A inhibitors should be avoided.^[1] If concomitant use cannot be avoided, the initial lorlatinib dosage should be reduced from 100 mg daily to 75 mg daily.^[1] In patients who have had a dosage reduction to 75 mg daily, the dosage of lorlatinib should be reduced to 50 mg daily during concomitant use with a potent CYP3A inhibitor.^[1] If concomitant use of the potent CYP3A inhibitor is discontinued, the lorlatinib dosage should be increased back to the dosage that was tolerated prior to initiation of the potent CYP3A inhibitor after 3 plasma half-lives of the potent CYP3A inhibitor have elapsed.^[1]

Concomitant use of lorlatinib with fluconazole may also increase plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse effects.^[1] Concomitant use of lorlatinib with fluconazole should be avoided.^[1] If concomitant use cannot be avoided, the initial lorlatinib dosage should be reduced from 100 mg daily to 75 mg daily.^[1]

Drugs Metabolized by Hepatic Microsomal Enzymes

Lorlatinib is a moderate inducer of CYP3A.^[1] Concomitant use of lorlatinib and drugs metabolized by CYP3A may result in decreased concentrations and reduced efficacy of the CYP3A substrate.^[1] When lorlatinib (150 mg daily for 15 days) was administered concurrently with midazolam (single 2-mg oral dose), peak plasma concentrations and AUC of midazolam decreased by 50 and 64%, respectively.^[1] When lorlatinib (100 mg once daily) was administered concomitantly with bupropion (CYP2B6 substrate) and tolbutamide (CYP2C9 substrate), peak plasma concentration and AUC of the substrate drugs were decreased.^[1]

Concomitant use of lorlatinib and CYP3A substrates where minimal concentration changes may result in serious therapeutic failure should be avoided.^[1] If concomitant use cannot be avoided, dosage adjustment of the CYP3A substrate may be required; specific product labeling for the CYP3A substrate should be consulted.^[1]

Drugs Affected by Transport Systems

Concomitant use of lorlatinib and P-gp or UGT1A substrates may result in decreased concentrations and reduced efficacy of the P-gp or UGT1A substrate.^[1] When lorlatinib (100 mg once daily) was administered concomitantly with fexofenadine (P-gp substrate) and acetaminophen (UGT1A substrate), peak plasma concentration and AUC of the substrate drugs were decreased.^[1]

Avoid concomitant use of lorlatinib and P-gp substrates with a narrow therapeutic index.^[1] If concomitant use cannot be avoided, consult the manufacturer's labeling of the P-gp substrate for dosage recommendations.^[1]

Drugs Affecting Gastric pH

Concomitant administration of lorlatinib and the proton-pump inhibitor rabeprazole did not have a clinically important effect on the pharmacokinetics of lorlatinib.^[1]

Hormonal Contraceptives

Concomitant use of lorlatinib and hormonal contraceptives may result in reduced efficacy of the hormonal contraceptive.^[1] Women of childbearing potential should therefore use effective nonhormonal contraception during lorlatinib therapy and for at least 6 months after the drug is discontinued.^[1]

Fluconazole

Concomitant use of lorlatinib with fluconazole may increase plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse effects.^[1]

Concomitant use of lorlatinib with fluconazole should be avoided.^[1] If concomitant use with fluconazole cannot be avoided, the initial dosage of lorlatinib should be reduced from 100 mg once daily to 75 mg once daily.^[1]

Lorlatinib, an inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase (ALK) and c-ros oncogene-1 (ROS1) as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK, is an antineoplastic agent.^{[1][2][3][13]} The drug inhibits phosphorylation of ALK^[1] and ALK-mediated signal transduction, specifically STAT3, AKT, ERK, and S6.^[13]

Activating mutations or translocations of the ALK gene have been identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).^{[3][8][9][10][11]} Such ALK gene rearrangements have been identified in approximately 3-7% of patients with non-small cell lung cancer (NSCLC).^{[2][8][9][10]} Formation of ALK fusion proteins such as EML4-ALK results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.^[9][10][11]

Although the ALK inhibitor crizotinib has demonstrated improved outcomes in patients with NSCLC harboring ALK mutations, secondary resistance to crizotinib eventually develops, generally within the first 1-2 years of treatment.^{[2][8][9][11]} Clinical resistance to crizotinib has been attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways.^{[2][5][8][9][11][13]} More potent ALK inhibitors (e.g., alectinib, ceritinib) were developed to overcome resistance to crizotinib; however, resistance to these drugs also develops over time.^[2][5][13] Secondary mutations of ALK are responsible for about 30% of cases of acquired crizotinib resistance^[6][11][13] while about 50% of cases of acquired resistance to other ALK inhibitors are attributed to ALK mutations, with G1202R predominating.^[5] The CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF;^{[3][6][8][9][11][13]} development and/or progression of brain metastases occurs in approximately one-third to one-half of patients during crizotinib treatment.^[6][8][13]

In vitro, lorlatinib demonstrates greater potency than alectinib, ceritinib, and crizotinib in its activity against wild-type ALK and is active against cell lines expressing ALK mutations that confer resistance to crizotinib, including G1202R (which also confers resistance to alectinib and ceritinib), G1269A, and L1196M.^{[2][3][5][6][13]} Lorlatinib also demonstrated dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts that expressed EML4-ALK fusions with either ALK variant 1 or ALK mutations, including G1202R and I1171T mutations that were detected in tumors of patients at the time of disease progression in patients receiving therapy with other ALK inhibitors.^[1][13] Lorlatinib also demonstrated antitumor activity and prolonged survival in mice bearing intracranial EML4-ALK-positive tumor xenografts^[1][3][13] and antitumor activity in patients with CNS metastases who had received prior treatment with other ALK inhibitors (e.g., alectinib, ceritinib, crizotinib).^[1][2]

Peak plasma concentration of lorlatinib is dose proportional and systemic exposure to lorlatinib is slightly less than dose proportional at steady state over the oral dosage range of 10-200 mg once daily.^[1] Following oral administration, peak plasma concentrations of lorlatinib are achieved at a median of 1.2 hours.^[1] The mean absolute bioavailability of lorlatinib is 81%.^[1] Administration of lorlatinib with a high-fat, high-calorie meal has no clinically important effect on the pharmacokinetics of lorlatinib.^[1] Lorlatinib is 66% bound to plasma proteins in vitro and is distributed into CSF at a CSF-to-plasma ratio of 0.75.^[1][3] Lorlatinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions by CYP isoenzymes 2C8, 2C19, and 3A5, and UGT1A3.^[1] The major metabolite, M8, is pharmacologically inactive.^[1] Following oral administration of a single dose of radiolabeled lorlatinib, 48% of the dose is eliminated in urine (less than 1% as unchanged drug) and 41% of the dose is eliminated in feces (about 9% as unchanged drug).^[1] Oral clearance of lorlatinib is higher at steady state than following a single dose, suggesting that autoinduction occurs.^[1] The mean plasma half-life of lorlatinib is 24 hours.^[1] Age (19-85 years), sex, race/ethnicity, body weight, and CYP3A5 or CYP2C19 metabolizer phenotypes do not have clinically important effects on the pharmacokinetics of lorlatinib.^[1]

Importance of reading the manufacturer's patient information.^[1]Importance of advising patients to take lorlatinib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by their clinician.^[1] Importance of advising patients to swallow lorlatinib tablets whole without regard to food and not to crush, chew, or split the tablets.^[1] If a dose is missed, the missed dose should be taken as soon as possible unless it is within 4 hours of the next dose, in which case the missed dose should not be taken.^[1] Inform patients to not take 2 doses at the same time to make up for a missed dose.^[1] If vomiting occurs after taking a dose, the next dose should be taken at the regularly scheduled time; an additional dose should not be taken.^[1]Risk of severe hepatotoxicity when used concomitantly with potent CYP3A inducers.^[1]Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs (e.g., antilipemic agents, rifampin, oral contraceptives), OTC drugs, and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses (e.g., history of depression or other mood disorders, hyperlipidemia, cardiac arrhythmias, pulmonary disease).^[1]Risk of adverse CNS effects.^[1] Patients should notify their clinician if they experience new or worsening CNS symptoms such as changes in cognitive function or mood, suicidal ideation, hallucinations, or seizures.^[1]Risk of hyperlipidemia.^[1] Importance of informing patients about the need for monitoring serum cholesterol and triglyceride concentrations during therapy.^[1] Advise patients that initiation of antilipemic therapy or an increase in the dosage of existing antilipemic agents may be required.^[1]Risk of AV block.^[1] Importance of patients immediately contacting their clinician if they experience new or worsening cardiac symptoms such as dizziness, faintness, or arrhythmia during therapy.^[1]Risk of severe or life-threatening ILD/pneumonitis.^[1] Importance of advising patients that symptoms may be similar to those of lung cancer and to contact their clinician immediately if they experience any new or worsening respiratory symptoms (e.g., dyspnea or shortness of breath, cough, fever).^[1]Risk of hypertension.^[1] Importance of advising patients to monitor blood pressure regularly.^[1] Advise patients that initiation or optimization of blood pressure medications may be necessary during lorlatinib therapy.^[1] Importance of immediately informing clinician if signs or symptoms of hypertension, including headaches, dizziness, blurred vision, chest pain, or shortness of breath occur.^[1]Risk of hyperglycemia.^[1] Importance of advising patients that regular monitoring of blood glucose may be needed prior to and during treatment with lorlatinib.^[1] Patients should be advised of the possible need to change or start medications for hyperglycemia.^[1] Importance of informing clinician of new or worsening signs and symptoms of hyperglycemia, including increased thirst, increased need to urinate, increased hunger, nausea, weakness or tiredness, or confusion.^[1]Risk of fetal harm.^[1] Necessity of advising females of reproductive potential that they should use effective, nonhormonal methods of contraception while receiving lorlatinib and for >=6 months after discontinuance of therapy and of also advising such females that oral contraceptives and other hormonal forms of contraception may not be effective during lorlatinib therapy.^[1] Importance of advising males with female partners of reproductive potential to use effective methods of contraception while receiving the drug and for >=3 months after the drug is discontinued.^[1] Importance of also advising males of reproductive potential that lorlatinib may transiently impair fertility and to discuss any concerns about fertility with their clinician.^[1]Importance of females informing their clinicians if they are or plan to become pregnant.^[1] Advise of potential fetal risk.^[1]Importance of advising females to avoid breast-feeding while receiving lorlatinib and for 7 days after discontinuance of therapy.^[1]Importance of informing patients of other important precautionary information.^[1] (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lorlatinib is available through specialty pharmacies.^[12] Clinicians may consult the Lorbrena^® website for specific information regarding distribution of the drug.^[12]

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