Lorlatinib

Approved Indications:

• ALK-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC):
  Lorlatinib is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC whose disease has progressed on:
• Crizotinib and at least one other ALK inhibitor (e.g., ceritinib or alectinib), or
• Alectinib or ceritinib as first ALK inhibitor therapy for metastatic disease.

Clinically Accepted Off-Label Use:

• ROS1-Positive NSCLC (Investigational use):
  Though not FDA-approved, lorlatinib has shown clinical activity in ROS1-rearranged NSCLC, particularly after failure of first-line ROS1 inhibitors (like crizotinib), but usage is guided by emerging data and requires individualized risk-benefit assessment.

General Administration:

• Route: Oral
• Frequency: Once daily
• Taken with or without food
• Tablets must be swallowed whole (do not crush, chew, or split)

Adult Dosage:

• Recommended Dose: 100 mg orally once daily
• Treatment Duration: Continue until disease progression or unacceptable toxicity

Pediatric Use:

• Not established. Safety and efficacy in patients <18 years have not been determined.

Elderly:

• No specific dose adjustment based solely on age; however, monitor closely for increased risk of adverse effects.

Renal Impairment:

• Mild to moderate impairment (CrCl ≥30 mL/min): No dosage adjustment required
• Severe renal impairment (CrCl <30 mL/min): Safety not established

Hepatic Impairment:

• Mild hepatic impairment (Child-Pugh A): No dose adjustment needed
• Moderate to severe hepatic impairment (Child-Pugh B or C): Not recommended due to lack of data

Dose Modifications for Toxicities:

• Grade 2 CNS effects or Grade ≥3 laboratory abnormalities (e.g., hyperlipidemia, hepatotoxicity) may require dose interruption, reduction (75 mg or 50 mg once daily), or discontinuation depending on severity and recurrence.

Lorlatinib is a third-generation tyrosine kinase inhibitor (TKI) that selectively inhibits anaplastic lymphoma kinase (ALK) and ROS1 kinases, including mutated forms resistant to earlier-generation ALK inhibitors. It binds to the ATP-binding domain of ALK and ROS1, blocking phosphorylation of downstream signaling proteins such as STAT3 and PI3K-AKT. This inhibition disrupts cell proliferation and survival pathways in ALK-driven tumor cells. Lorlatinib is uniquely designed to penetrate the blood-brain barrier, offering efficacy against brain metastases.

• Absorption: Rapidly absorbed; peak plasma concentration occurs within 1–2 hours
• Bioavailability: Approx. 81%
• Distribution: Widely distributed; high volume of distribution; penetrates CNS
• Plasma Protein Binding: ~66%
• Metabolism: Primarily metabolized by CYP3A4 and UGT1A4; major active metabolite: PF-06895751
• Elimination Half-Life: Approximately 24 hours
• Excretion:
• ~47.7% via urine (minor unchanged)
• ~40.9% via feces
• Steady-State: Achieved by Day 15 with once-daily dosing

• Pregnancy Risk:
  Lorlatinib may cause fetal harm based on its mechanism of action and animal studies.
  FDA Pregnancy Category: Not assigned (Use only if potential benefit justifies potential risk)
  Contraception required during treatment and for at least 6 months after the last dose (females) or 3 months (males).
• Lactation:
  Unknown whether lorlatinib is excreted in human milk. Due to potential for serious adverse reactions in infants, breastfeeding is not recommended during treatment and for 7 days after the last dose.

• Primary Class: Antineoplastic agent
• Subclass: Tyrosine Kinase Inhibitor (ALK and ROS1 inhibitor)
• Generation: Third-generation ALK TKI

• Hypersensitivity to lorlatinib or any excipients
• Co-administration with strong CYP3A inducers (e.g., rifampin, carbamazepine, St. John’s wort) due to risk of loss of efficacy
• Severe hepatic impairment (due to lack of data)

• CNS Effects: Cognitive effects (e.g., memory impairment, confusion), mood changes, and speech disorders; monitor regularly
• Hyperlipidemia: Common and severe elevations in cholesterol and triglycerides; monitor before and during treatment; may require statin therapy
• Cardiac: PR prolongation and AV block reported; monitor ECG in patients with conduction abnormalities
• Interstitial Lung Disease (ILD)/Pneumonitis: Can be life-threatening; permanently discontinue if suspected
• Hepatotoxicity: Monitor liver enzymes; interrupt or reduce dose if elevated
• Hyperglycemia: Reported in some patients; monitor glucose
• Teratogenicity: Embryo-fetal toxicity; avoid pregnancy
• Drug Interactions: Avoid CYP3A inducers/inhibitors; may alter lorlatinib levels

Common Adverse Effects (≥20%):

• Metabolic: Hypercholesterolemia, hypertriglyceridemia
• Neurologic/CNS: Cognitive dysfunction, mood changes, peripheral neuropathy, seizures
• Gastrointestinal: Diarrhea, nausea, vomiting, constipation
• General: Fatigue, edema, weight gain
• Dermatologic: Rash

Serious or Rare Effects:

• Interstitial lung disease/pneumonitis
• Second-degree or complete AV block
• Seizures
• Hepatotoxicity
• Visual disturbances

Timing & Severity:

• CNS effects typically appear within the first few weeks of therapy
• Hyperlipidemia often develops early and is dose-dependent
• Dose adjustments may reduce symptom severity

• Strong CYP3A Inducers (e.g., rifampin, phenytoin): Contraindicated – can significantly reduce lorlatinib plasma levels
• Strong CYP3A Inhibitors (e.g., itraconazole, clarithromycin): Avoid or monitor for increased toxicity
• CYP3A Substrates (e.g., midazolam): Lorlatinib induces CYP3A and may reduce substrate effectiveness
• CYP2B6 Induction: May decrease exposure to CYP2B6 substrates
• P-gp and BCRP Inhibition: Lorlatinib may increase plasma levels of co-administered P-gp/BCRP substrates
• Statins: Dose adjustment may be required due to interaction with lipid-lowering agents

• FDA Label Update (Recent Years): Expanded warnings for CNS effects and hyperlipidemia monitoring
• Guidelines:
• NCCN and ESMO guidelines recommend lorlatinib as second- or third-line therapy for ALK-positive NSCLC following failure of other ALK inhibitors
• Emerging evidence supports use in managing CNS metastases, even at early stages

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C
• Humidity: Keep in a dry place
• Light: Store in original container to protect from light
• Handling Precautions: Keep out of reach of children. Do not crush or split tablets. No refrigeration required.
• Disposal: Dispose of unused medicine according to local regulations for cytotoxic agents