Larotrectinib

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Characteristics

Larotrectinib (LOXO-101), a highly selective TRK inhibitor, is a CNS active small molecule tyrosine kinase inhibitor of the three TRK protein kinases [1-5]. Larotrectinib pharmacokinetics (PK) are conducive to oral dosing and its pharmacokinetics are similar between 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 has been approved for clinical use 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.

Larotectinib is the first therapy to receive a tumour-agnostic indication at the time of initial FDA approval in 2018 via a priority review pathway [5].

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.

In addition, larotrectinib was granted orphan designation for the treatment of salivary gland cancer by the European Medicines Agency (EMA) in March 2018 [6]. A marketing application for larotrectinib was submitted subsequently to the EMA in August 2018 [7].

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. Loxo Oncology. VITRAKVI® (larotrectinib) [prescribing information]. In. Stamford, CT: Loxo Oncology, Inc. 2018.
  6. European Medicines Agency. EU/3/18/1995. 2018.
  7. Loxo Oncology. Loxo Oncology Announces Submission of European Marketing Authorization Application for Larotrectinib. 2018.