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
- 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.
- 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.
- Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
- 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.
- Loxo Oncology. VITRAKVI® (larotrectinib) [prescribing information]. In. Stamford, CT: Loxo Oncology, Inc. 2018.
- European Medicines Agency. EU/3/18/1995. 2018.
- Loxo Oncology. Loxo Oncology Announces Submission of European Marketing Authorization Application for Larotrectinib. 2018.