Larotrectinib

Larotrectinib is a tropomyosin receptor kinase (TRK) inhibitor and the primary representative of a relatively new class of drugs approved specifically for the treatment of rare cancers with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion (see TRK inhibitors below).

Larotrectinib is an adenosine triphosphate (ATP)-competitive and selective tropomyosin receptor kinase(TRK) inhibitor. TRK fusion tumors arise from neurotrophic tyrosine receptor kinase (NTRK) gene fusions. The resulting novel chimeric oncogenic proteins are aberrantly expressed and lead to constitutive kinase activity with activation of downstream cellular signaling pathways involved in cell proliferation and survival, resulting in TRK fusion-positive tumors.

NTRK gene fusions occur with high incidence in infantile fibrosarcoma (>90%) or the secretory form of breast carcinoma (>90%). In spitzoid melanoma, NTKR gene fusions are present with a prevalence of 21-29%, in cutaneous melanoma with <1% and in acral and mucosal melanoma with 2.5%. As TRK inhibitors such as larotrectinib are available for patients with NTRK gene fusions, screening for this gene fusion should be implemented clinically (Forschner A et al. 2020).

In a study involving 17 different cancer types with NTRK fusions, including 7 melanoma patients, larotrectinib showed a high overall response rate of 76%, which lasted >12 months in 71% of patients (Drilon AE et al. 2019). Loratrectinib showed antitumor activity in patients of all ages (Forschner a et al. 2020) . It appears that fusion proteins and the usual oncogenic drivers such as BRAF, NRAS, HRAS, GNAQ, GNA11 are mutually exclusive (Solomon JP et al. 2020).

Absorption: After administration of a single oral dose of 100 mg, the mean absolute bioavailability of larotrectinib was 34%. Maximum plasma concentrations (cmax) of larotrectinib are reached approximately 1 hour after oral administration. The half-life (t1/2) is approximately 3 hours and steady state is reached within 8 days with a systemic accumulation of 1.6-fold.

Distribution: The mean volume of distribution of larotrectinib in healthy adult volunteers was 48 L, indicating mean distribution from plasma to tissues. Plasma protein binding was approximately 70% in vitro and was independent of drug concentration.

Biotransformation: Larotrectinib is metabolized in vitro predominantly by CYP3A4/5.

Elimination: The half-life of larotrectinib in plasma was approximately 3 hours in tumor patients receiving 100 mg larotrectinib twice daily. After oral administration of 100 mg radiolabeled larotrectinib, 58% of the administered radioactivity was recovered in the faeces and 39% in the urine.

Larotrectinib is available as an oral therapeutic agent and has been approved as a capsule or solution with equivalent oral bioavailability since October 15, 2019. The substance is used as monotherapy for the treatment of adult and pediatric patients with solid tumors with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion in the following conditions

• locally advanced or metastatic disease
• disease where surgical resection is likely to result in severe morbidity
• no satisfactory treatment options are available
• Cases with NGS-based confirmation of the NTRK fusion(Penault-Liorca F et al. 2019)

Pregnancy: To date, there is no experience with the use of larotrectinib in pregnant women. Animal studies have not shown any evidence of direct or indirect adverse health effects related to reproductive toxicity. However, for precautionary reasons, use during pregnancy should be avoided.

Lactation: It is not known whether larotrectinib or its metabolites pass into breast milk. Since a risk to the newborn/infant cannot be excluded, breastfeeding should be discontinued during treatment and for 3 days after the last dose.

In adults, the recommended dose is 100 mg larotrectinib twice daily until disease progression or unacceptable toxicity occurs.

In children and adolescents, the dosage is based on the body surface area (BSA). The recommended dose is 100 mg/m2 larotrectinib twice daily (maximum 100 mg per dose) until disease progression or unacceptable toxicity occurs.

The most common side effects (≥ 20%) of larotrectinib in descending frequency were:

• fatigue (32%)
• increased ALT (31%)
• dizziness (30%)
• increased AST (29%)
• constipation (29%)
• Nausea (26%)
• anemia (24%)
• vomiting (20%)
• In 3% of treated patients, larotrectinib was permanently discontinued due to treatment-related side effects.

Larotrectinib is a substrate of cytochrome P450 (CYP) 3A, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Strong CYP3A, P-gp and BCRP inhibitors may increase the plasma concentration of larotrectinib when used concomitantly. These include: atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole or grapefruit.

Strong or moderate CYP3A and P-gp inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin or St. John's wort may reduce the plasma concentrations of larotrectinib when used concomitantly. The concomitant use of CYP3A substrates with a narrow therapeutic range (e.g. alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus) should be carried out with caution. In vitro studies also indicate that larotrectinib is an inducer of CYP2B6. Concomitant use may reduce the exposure of CYP2B6 substrates (e.g. bupropion, efavirenz).

Furthermore, it cannot be ruled out that the use of larotrectinib together with OATP1B1 substrates (e.g. valsartan, statins) may increase their exposure. Concomitant administration of larotrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may reduce their exposure. Women using systemic hormonal contraceptives should be advised to use an additional barrier method, as it is not known whether larotrectinib can reduce their effectiveness.

Larotrectinib must not be used in cases of known hypersensitivity to the active substance.

Ability to drive: Larotrectinib has a moderate influence on the ability to drive and use machines. During the first 3 months of treatment, dizziness and fatigue may occur, which may affect the ability to drive and use machines.

1. Drilon A (2019) RK inhibitors in TRK fusion-positive cancers. Ann Oncol 30 Suppl 8:viii23-viii30.
2. Forschner A et al. (2020) NTRK gene fusions in melanoma: diagnostics, prevalence and potential therapeutic relevance. J Dtsch Dermatol Ges 18:1387-1393
3. Penault-Llorca F et al (2019) Testing algorithm for identification of patients with TRK fusion cancer. J Clin Pathol 72: 460-467.
4. Solomon JP et al. (2020) NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol 33:38-46
5. Yang JCH et al. (2022) Rationale and design of ON-TRK: a novel prospective non-interventional study in patients with TRK fusion cancer treated with larotrectinib. BMC Cancer 22:625.