Lotenib

Approved Indications (FDA/EMA):

• Solid Tumors with NTRK Gene Fusion:
  Larotrectinib is indicated for the treatment of adult and pediatric patients with solid tumors that:
• Have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation,
• Are metastatic or where surgical resection is likely to result in severe morbidity, and
• Have no satisfactory alternative treatments or have progressed following prior therapy.
  This is a tissue-agnostic indication, approved regardless of tumor origin.

Clinically Accepted Off-label Uses:

• Infantile Fibrosarcoma with NTRK Fusion: Used in neonates and infants, particularly in unresectable or metastatic cases.
• Neoadjuvant Therapy: In large or borderline resectable NTRK fusion-positive tumors, especially in pediatric patients, to shrink tumors preoperatively.
• Refractory NTRK+ Cancers: Including thyroid, salivary gland, colorectal, lung, and pancreatic carcinomas when standard therapies fail.

Route of Administration: Oral

Formulations:

• Capsules: 25 mg, 100 mg
• Oral Solution: 20 mg/mL

Adults:

• 100 mg orally twice daily (every 12 hours), continuously until disease progression or unacceptable toxicity.

Pediatrics:

• Children <20 kg: 100 mg/m² orally twice daily.
• Children ≥20 kg: 100 mg orally twice daily.

Elderly:

• No dose adjustment required; monitor for tolerability.

Renal Impairment:

• No dosage adjustment needed in mild to moderate renal impairment.
• Use caution in severe renal impairment due to limited data.

Hepatic Impairment:

• Mild (Child-Pugh A): No adjustment.
• Moderate or Severe (Child-Pugh B or C): Reduce dose by 50%.

Administration Instructions:

• May be taken with or without food.
• Shake oral solution well before use.
• Administer doses approximately 12 hours apart.

Larotrectinib is a highly selective inhibitor of the TRK family of proteins (TRKA, TRKB, TRKC), which are encoded by NTRK1, NTRK2, and NTRK3 genes, respectively. In cancers harboring NTRK gene fusions, the resultant fusion proteins are constitutively active and drive oncogenic signaling through MAPK, PI3K, and PLCγ pathways, leading to uncontrolled cell proliferation. Larotrectinib binds to the ATP-binding site of these TRK proteins, preventing their phosphorylation and downstream signaling. This inhibition suppresses tumor cell growth and induces apoptosis, providing potent antitumor activity in NTRK fusion-positive malignancies.

• Absorption: Rapidly absorbed; peak plasma concentration (Tmax) ~1 hour post-dose.
• Bioavailability: High.
• Distribution: Volume of distribution ~48 L. Moderate plasma protein binding (~70%).
• Metabolism: Extensively metabolized by CYP3A4; one major active metabolite.
• Elimination Half-Life:
• Parent drug: ~3 hours
• Active metabolite: ~6 hours
• Excretion:
• Feces: ~58%
• Urine: ~39% (mostly as metabolites)
• Steady-State: Achieved within 3 days with twice-daily dosing.

Pregnancy:

• FDA Category: Not assigned (under new labeling system)
• Animal studies have shown developmental toxicity (skeletal abnormalities, embryo-fetal lethality).
• Use during pregnancy only if the potential benefit justifies the risk.

Lactation:

• Unknown if larotrectinib is excreted in human breast milk.
• Due to the potential for serious adverse effects in nursing infants, breastfeeding is not recommended during treatment and for at least 1 week after the final dose.

Pregnancy:

• FDA Category: Not assigned (under new labeling system)
• Animal studies have shown developmental toxicity (skeletal abnormalities, embryo-fetal lethality).
• Use during pregnancy only if the potential benefit justifies the risk.

Lactation:

• Unknown if larotrectinib is excreted in human breast milk.
• Due to the potential for serious adverse effects in nursing infants, breastfeeding is not recommended during treatment and for at least 1 week after the final dose.

• Known hypersensitivity to larotrectinib or any of its components.
• Co-administration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine), unless no alternatives exist.
• Severe hepatic impairment without appropriate dose adjustment.

• Neurotoxicity: May cause dizziness, ataxia, confusion; monitor for neurologic symptoms and advise caution with activities requiring mental alertness.
• Hepatotoxicity: Elevated liver enzymes may occur. Monitor ALT and AST before treatment and regularly during therapy.
• Myelosuppression: Monitor complete blood counts (CBC); anemia and neutropenia have been reported.
• Hypersensitivity: Rare hypersensitivity reactions, including anaphylaxis, may occur.
• Resistance Mutations: Patients may develop TRK mutations (e.g., G595R) leading to treatment resistance.

Very Common (≥10%):

• Fatigue
• Dizziness
• Nausea
• Vomiting
• Constipation
• Diarrhea
• Increased AST/ALT
• Anemia
• Weight gain

Common (1%–10%):

• Headache
• Myalgia
• Cough
• Neutropenia
• Increased creatinine

Rare but Serious (<1%):

• Severe neurotoxicity (ataxia, cognitive impairment)
• Hepatotoxicity
• Hypersensitivity reactions

Timing & Severity:

• Adverse effects are generally mild to moderate.
• Most occur within the first month of therapy and may be reversible with dose adjustment.

• CYP3A4 Inhibitors (e.g., itraconazole): May increase plasma levels of larotrectinib; consider dose reduction.
• CYP3A4 Inducers (e.g., rifampin, phenytoin): May significantly reduce drug efficacy; avoid if possible.
• CYP3A4 Substrates (e.g., midazolam, cyclosporine): Larotrectinib may increase plasma concentrations; monitor closely.
• Food: No significant interactions; may be administered with or without food.
• Alcohol: Not contraindicated, but may increase CNS side effects such as dizziness.

• FDA & EMA Updates: Continued support for tissue-agnostic use in NTRK fusion-positive cancers.
• EMA 2023 Update: Expanded pediatric data for use in infantile fibrosarcoma.
• Ongoing Trials: Resistance management with second-line TRK inhibitors like selitrectinib is under investigation.
• NCCN Guidelines: Endorse larotrectinib for all confirmed NTRK fusion-positive tumors when standard treatment is ineffective or not tolerated.

• Capsules and Oral Solution:
• Store at 20°C to 25°C (68°F to 77°F).
• Allowable excursion range: 15°C to 30°C.
• Protect from moisture and direct light.
• Oral Solution:
• Do not refrigerate or freeze.
• Shake well before use.
• Use within 90 days of opening.