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Characteristics

Larotrectinib (LOXO-101), a highly selective TRK inhibitor, is a small molecule tyrosine kinase inhibitor with potent activity against TRKA, TRKB, and TRKC [1-4]. Larotrectinib pharmacokinetics (PK) are conducive to oral dosing and can be used in for both, adult and paediatric patients [5].

Table 3: Pharmacokinetic Profile of Larotrectinib[5]

Parameter

Value or characteristic

Maximum plasma concentration

1-hour post-dosing

Exposure

Similar following single or continuous dosing

Bioavailabilitya

34%

Mean clearance

98 L/hour

Half life

2.9 hours

Excretion

58% recovered in faeces and 39% in urine

aMean absolute bioavailability

Larotrectinib is the first NTRK targeting therapy to receive a tumour-agnostic approval by the US Food and Drug Administration (FDA) [5] for the treatment of adult and paediatric patients with solid tumours that [5]:

  • Have an NTRK gene fusion without a known acquired resistance mutation,
  • Are metastatic or in which surgical resection is likely to cause severe morbidity, and
  • Have no satisfactory alternative treatments or that have progressed following treatment.

EMA approved larotrectinib as monotherapy for the treatment of adult and paediatric patients with solid tumours that display a NTRK gene fusion who 1) have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and 2) have no satisfactory treatment options starting from first-line [6].

Larotrectinib is available as oral capsules or in a liquid formulation [5]. The recommended dose is based on body surface area (BSA):

  • 100 mg orally twice daily for adults and children with a BSA ≥1.0 m2.
  • 100 mg/m2 orally twice daily for paediatric patients with BSA <1.0 m2.

References

  1. Burris HA, Shaw AT, Bauer TM et al. Abstract 4529: Pharmacokinetics (PK) of LOXO-101 during the first-in-human Phase I study in patients with advanced solid tumors: Interim update. Cancer Research 2015; 75: 4529.
  2. Drilon A, Laetsch TW, Kummar S et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 2018; 378: 731-739.
  3. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
  4. Laetsch TW, DuBois SG, Nagasubramanian R et al. A pediatric phase I study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family. Journal of Clinical Oncology 2017; 35: 10510-10510.
  5. VITRAKVI® (larotrectinib), USA Prescribing Information. 2021.

  6. VITRAKVI® (larotrectinib), EMA Summary of medicinal Product Characteristics. 2022.

Clinical Data

Larotrectinib efficacy and safety have been evaluated in three clinical trials in patients with cancers with NTRK gene fusion.

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