Lorlatinib as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after Alectinib or Ceritinib as the first ALK inhibitor therapy, or after Crizotinib and at least one other ALK inhibitor.

Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1, as well as several other kinases including TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. It has shown activity against multiple mutant forms of the ALK enzyme, including mutations that may develop after progression on crizotinib and other ALK inhibitors. In animal studies, Lorlatinib demonstrated dose-dependent antitumor activity and prolonged survival in tumors driven by EML4-ALK alterations, including tumors implanted in the brain. Its overall antitumor effect is associated with inhibition of ALK phosphorylation.

The recommended dose is 100 mg Lorlatinib taken orally once daily. Treatment with Lorlatinib is recommended as long as the patient is deriving clinical benefit from therapy without unacceptable toxicity. If a dose of Lorlatinib is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.

Dosing interruption or dose reduction may be required based on individual safety and tolerability. Lorlatinib dose reduction levels are summarized below:

• First dose reduction: 75 mg taken orally once daily.
• Second dose reduction: 50 mg taken orally once daily.

Lorlatinib should be permanently discontinued if the patient is unable to tolerate the 50 mg dose taken orally once daily.

CYP3A4/5 substrates: In vitro data show that Lorlatinib acts as both a time-dependent inhibitor and an inducer of CYP3A4/5, activating the human pregnane X receptor (PXR), with the overall in vivo effect being induction. Co-administration of Lorlatinib has been shown to decrease oral midazolam exposure compared to midazolam alone, indicating CYP3A4/5 induction. Administration of Lorlatinib 150 mg once daily for 15 days reduced AUCinf and Cmax of a single 2 mg dose of midazolam by approximately 61% and 50%, respectively. Therefore, Lorlatinib is considered a moderate CYP3A inducer. Concomitant use with CYP3A4/5 substrates with narrow therapeutic ranges—such as alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus, and tacrolimus—should be avoided due to reduced drug concentrations.

In vitro studies of other CYP inhibition and induction: Lorlatinib may inhibit CYP2C9 and has been shown to induce CYP2B6 through activation of the constitutive androstane receptor (CAR). Co-administration with CYP2B6 substrates (e.g., bupropion, efavirenz) may decrease their plasma levels. Lorlatinib has a low potential to cause drug interactions via CYP1A2 induction.

In vitro studies of UGT inhibition: Lorlatinib may inhibit UGT1A1 based on in vitro findings.

In vitro studies with drug transporters: Lorlatinib may inhibit several transporters including P-glycoprotein (P-gp; both systemic and gastrointestinal), BCRP (gastrointestinal tract), OATP1B1, OATP1B3, OCT1, MATE1, and OAT3 at clinically relevant concentrations.

Lorlatinib is contraindicated in patients with hypersensitivity to Lorlatinib and in patients receiving strong CYP3A4/5 inducers concomitantly.

The most frequently reported adverse reactions with Lorlatinib include hypercholesterolaemia, hypertriglyceridaemia, oedema, peripheral neuropathy, cognitive effects, fatigue, weight gain, and mood effects. Dose reduction may be needed in some patients, especially due to oedema or peripheral neuropathy. In a smaller number of patients, permanent treatment discontinuation was required, most commonly because of cognitive effects.

Women of Childbearing Potential / Contraception in Males and Females: Women of childbearing potential should avoid pregnancy while taking Lorlatinib. A highly effective non-hormonal contraceptive method is recommended for female patients, as Lorlatinib may reduce the effectiveness of hormonal contraceptives. If hormonal contraception is necessary, it should be combined with a barrier method such as a condom. Contraception should be continued for at least 35 days after completion of therapy. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 14 weeks after the last dose. Male patients with pregnant partners should use condoms.

Pregnancy: Animal studies have demonstrated embryo-fetal toxicity. There are no adequate data on the use of Lorlatinib in pregnant women. Lorlatinib may cause fetal harm if administered during pregnancy and is not recommended for use in pregnant women or in women of childbearing potential who are not using contraception.

Breast-feeding: It is unknown whether Lorlatinib or its metabolites are excreted in human milk. A potential risk to infants cannot be excluded. Breastfeeding should be discontinued during treatment and for at least 7 days after the final dose of Lorlatinib.

Fertility: Based on non-clinical findings, Lorlatinib may impair male fertility. The effect on female fertility is not known. Men should consider seeking advice on fertility preservation before starting treatment.

Hyperlipidemia: The use of Lorlatinib has been associated with increases in serum cholesterol and triglycerides. Monitor lipid levels prior to initiation, at 1 and 2 months after starting treatment, and periodically thereafter. Initiate or adjust lipid-lowering therapy as clinically indicated.

Central nervous system effects: CNS effects have been observed, including changes in cognitive function, mood, speech, and behavior. Dose modification or discontinuation may be required depending on severity.

Atrioventricular block: Lorlatinib has been associated with AV block. Monitor ECG and electrolytes periodically. Withhold or permanently discontinue treatment based on severity.

Left ventricular dysfunction: Decreases in left ventricular ejection fraction (LVEF) have been reported. Monitor cardiac function during treatment. Dose interruption or discontinuation may be necessary.

Lipase and amylase increases: Elevations in lipase and/or amylase have been observed. Monitor levels before starting therapy and periodically during treatment.

Interstitial lung disease/Pneumonitis: Severe or life-threatening pulmonary adverse reactions may occur. Promptly evaluate patients presenting with respiratory symptoms. Permanently discontinue if confirmed.

Drug-drug interactions: Lorlatinib may interact with drugs that strongly inhibit or induce CYP3A. Avoid strong CYP3A inhibitors/inducers. Adjust doses of concomitant medications as needed.

Fertility and pregnancy: Lorlatinib may cause embryo-fetal harm. Effective contraception is required during treatment and for a specified period after the last dose.

Hepatic impairment: Monitor liver function tests before and during treatment. Use caution in patients with hepatic impairment.

Pharmacokinetic interactions: Lorlatinib is metabolized primarily by CYP3A4 and UGT1A4. Concomitant use with strong CYP3A modulators may significantly alter its exposure.

Elderly (≥65 years): Limited data are available; no specific dosage adjustment is recommended solely based on age.

Renal impairment: No dose adjustment is recommended for mild or moderate renal impairment. Data are limited in severe renal impairment; use with caution.

Hepatic impairment: No dose adjustment is recommended for mild hepatic impairment. Limited information is available for moderate to severe impairment; use cautiously.

Pediatric population: The safety and efficacy of Lorlatinib in pediatric patients have not been established.

Treatment of Lorlatinib overdose consists of general supportive care. Because of its dose-dependent effect on the PR interval, ECG monitoring is recommended. There is no specific antidote for Lorlatinib overdose.

Cytotoxic Chemotherapy.

Store below 30°C. Protect from moisture and light. Keep Lorlatinib out of the sight and reach of children.