Generic Name

Lorlatinib

Mechanism

• Selective ALK/ROS1 inhibition: Binds irreversibly to the ATP‑binding pocket, blocking downstream signaling pathways (Ras–MAPK, PI3K–Akt, STAT3).
• High affinity for on‑circuit and off‑circuit resistance mutations, including L1196M, G1202R, and F1174L.
• Excellent CNS bioavailability: Low molecular weight, lipophilic structure, and lack of efflux by P‑gp/MDR1 facilitate penetration into brain metastases.

Pharmacokinetics

• Absorption: Peak plasma concentration (Cmax) reached ~4 h post‑dose; ingestion with food (~1 g of fat) increases AUC by ~30 %.
• Metabolism: Primarily via cytochrome P450 3A4 (CYP3A4); minor contributions from CYP1A2 and P‑gp.
• Elimination: Biliary and fecal excretion; half‑life ~24 h (steady‑state achieved by 7 days).
• Drug interactions:
• Strong CYP3A4 inducers (rifampin, carbamazepine) ↓ plasma concentrations.
• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) ↑ exposures; dose adjustment required.

Indications

• ALK‑positive locally advanced or metastatic NSCLC refractory to or intolerant of crizotinib, ceritinib, and alectinib.
• Patients with brain metastases (or CNS disease) even while on prior ALK TKIs.
• May be used in earlier lines in select clinical trials for CNS‑protected therapy.

Contraindications

• Hypersensitivity to the drug or its excipients.
• Severe hepatic impairment (Child‑Pugh C): avoid.
• Pregnancy & lactation: Category X; teratogenic in animal studies – mandatory contraception for women of childbearing potential.
• Active interstitial lung disease: risk of pneumonitis.

*Warnings*
• Hyperlipidemia: ↑ total cholesterol, LDL, triglycerides; monitor labs.
• Peripheral edema & weight gain: often concurrent with CNS toxicity.
• Central nervous system effects: Confusion, mood changes, vision disturbances (blurred vision, plaques).
• Hepatotoxicity: ALT/AST elevations up to 3‑4× ULN.
• QTc prolongation: Rare; baseline & periodic ECG.

Dosing

• Standard regimen: 100 mg orally once daily, 28‑day cycle, continuous therapy.
• Staggered start: First 5 days at 100 mg bid (200 mg total) to reduce rash on first dose? *Not standard; use only per prescribing info.*
• Food effect: Can be taken with or without food; high‑fat meals may improve bioavailability.
• Dose modifications:
• ↓ 50 mg if grade ≥ 3 hyperlipidemia or grade 2–3 edema.
• Interrupt therapy for ≥ 7 days for ALT/AST ≥ 3× ULN with symptoms.
• Renal/hepatic compensation: Dose adjustment not required for mild–moderate renal disease; avoid in severe hepatic disease.

Adverse Effects

*Adverse effect monitoring:* keep high‑yield vigilance for neuro‑psychiatric signs and vision changes, as these may precede other toxicities.

Monitoring

• Baseline & every 4 weeks:
• Lipid panel (total cholesterol, LDL, triglycerides).
• LFTs (ALT, AST, ALP, bilirubin).
• CBC (esp. neutrophil count).
• ECG (for QTc).
• Imaging (CT/MRI) every 8–12 weeks for disease assessment.
• Post‑dose: Observe for CNS symptoms; prompt evaluation for confusion or hallucinations.
• Lifestyle counselling: Diet rich in omega‑3, exercise to mitigate dyslipidemia; encourage seizure precautions for rare neuro‑toxicity.

Clinical Pearls

• CNS‑penetrance advantage: Lorlatinib is the only approved ALK TKI with consistent demonstrated efficacy in brain metastases; consider it early in patients with symptomatic or radiographically active CNS disease.
• Sequential therapy logic: In patients who have progressed on alectinib, a short “wash‑out” of 4–6 weeks may help maximize lorlatinib efficacy by reducing drug‑induced cross‑resistance.
• Lipid management: Initiate statin therapy prophylactically if baseline LDL > 160 mg/dL, or early in therapy if any > 140 mg/dL. Fluvastatin is preferred due to low CYP3A interaction.
• Pregnancy avoidance: Male partners of women of childbearing potential should avoid exposure through semen—WHO sperm washing not advised.
• Dose reduction strategy: Instead of stopping therapy, a temporary dose interruption and subsequent re‑initiation at 50 mg can resolve grade 2‑3 toxicity while preserving disease control.
• Drug–drug synergy: Lorlatinib can be safely combined with immune checkpoint inhibitors (e.g., pembrolizumab) in selected clinical trials; watch for increased immune‑mediated adverse events.

Key take‑away: Lorlatinib offers a powerful, brain‑penetrant option for ALK‑positive NSCLC, but necessitates diligent monitoring for metabolic, hepatic, and CNS toxicity. Adjust dosing appropriately, counsel patients on lifestyle modifications, and coordinate multidisciplinary care for optimal outcomes.