Larotrectinib, a precision-targeted therapy against NTRK gene fusions, requires individualized dosage and administration based on the patient's tumor gene characteristics, individual circumstances, and treatment response.
Patient Selection
Patients should be selected for larotrectinib treatment based on the presence of NTRK gene fusions in the tumor specimen.
For patients with secretory breast cancer, mammary analogue secretory carcinoma (MASC), congenital mesodermal nephroma (CMN), or infantile fibrosarcoma, treatment may be considered if NTRK rearrangements have not been confirmed in the tumor specimen.
Recommended Dosage
Adult and pediatric patients with a body surface area ≥1 square meter
The recommended dose of larotrectinib is 100 mg orally twice daily, with or without food, until disease progression or unacceptable toxicity.
For pediatric patients with a body surface area <1 m²:
The recommended dose of larotrectinib is 100 mg/m² orally twice daily, with or without food, until disease progression or unacceptable toxicity occurs.
Dose Adjustment for Adverse Reactions:
For all other Grade 3 or 4 adverse reactions:
Discontinue larotrectinib until the adverse reaction resolves or improves to baseline or Grade 1. If the adverse reaction resolves within 4 weeks, treatment can be resumed at the next dose adjustment level. If the adverse reaction does not resolve within 4 weeks, larotrectinib should be permanently discontinued.
The recommended dose reduction regimen for larotrectinib in response to adverse reactions is as follows:
Note: Pediatric patients receiving 25 mg/m² orally twice daily should maintain this dose even if their body surface area exceeds 1 m² during treatment. The maximum dose for the third dose adjustment is 25 mg/m² orally twice daily.
Initial dose reduction: Adults and pediatric patients with a body surface area ≥1 m² receive 75 mg orally twice daily; pediatric patients with a body surface area <1 m² receive 75 mg/m² orally twice daily.
Second dose reduction: Adults and pediatric patients with a body surface area ≥1 m² receive 50 mg orally twice daily; pediatric patients with a body surface area <1 m² receive 50 mg/m² orally twice daily.
Third dose reduction: Adults and pediatric patients with a body surface area ≥1 m² receive 100 mg orally once daily; pediatric patients with a body surface area <1 m² receive 25 mg/m² orally twice daily.
Patients who still cannot tolerate larotrectinib after three dose adjustments should permanently discontinue the drug.
Dosage Adjustment for Hepatotoxicity
The recommended dosage adjustment regimen for larotrectinib in cases of abnormal liver function tests is as follows (ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal; severity grading is based on the National Cancer Institute's General Terminology for Adverse Events:
When AST or ALT ≥ 5 × ULN and bilirubin ≤ 2 × ULN: Discontinue larotrectinib until it returns to ≤ grade 1 or baseline levels. Resume medication at the next lower dose level. If grade 4 AST and... If ALT is elevated, discontinue use permanently.
When AST or ALT > 3 × ULN and total bilirubin > 2 × ULN (without other surrogate causes): permanently discontinue larotrectinib.
For CTCAE grade 2 elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), liver function should be monitored frequently as clinically necessary to determine whether to pause administration or reduce the dose.
Dose adjustment with potent CYP3A4 inhibitors:
Larotrectinib should be avoided in combination with potent CYP3A4 inhibitors. If co-administration is unavoidable, the larotrectinib dose should be reduced by 50%. After discontinuing the inhibitor for 3-5 elimination half-lives, the larotrectinib dose should be restored to the level before the co-administration of the inhibitor.
Dose Adjustment with Strong or Intermediate CYP3A4 Inducers:
Co-administration of larotrectinib with strong CYP3A4 inducers should be avoided. If co-administration with a strong CYP3A4 inducer is unavoidable, the larotrectinib dose should be doubled; similarly, when co-administered with an intermediate CYP3A4 inducer, the larotrectinib dose should also be doubled. After discontinuing the inducer for 3-5 elimination half-lives... Restore the larotrectinib dose to the level before co-administration of the inducer.
Dose Adjustment for Patients with Hepatic Impairment
For patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment, the starting dose of larotrectinib should be reduced by 50%.
Administration Method
If less than 6 hours have passed since the next scheduled dose, no missed dose needs to be taken.
If vomiting occurs after taking larotrectinib, take the next dose at the scheduled time.
Capsules should be swallowed whole with a small amount of water. Do not chew or crush the capsules.
