Larotrectinib

What it is and how it works

Mechanism of Action Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC 50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentration. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 . Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines.

Mechanism class: Tropomyosin Receptor Kinases Inhibitors

Indications

is indicated for the treatment of adult and pediatric patients with solid tumors that: • have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, • are metastatic or where surgical resection is likely to result in severe morbidity, and • have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that: • have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, • are metastatic or where surgical resection is likely to result in severe morbidity, and • have no satisfactory alternative treatments or that have progressed following treatment.

Dosage and administration (summary)

• Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion ( 2.1 , 14 ). • Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of at Least Meter-Squared: 100 mg orally twice daily • Recommended Dosage in Pediatric Patients with Body Surface Area of Less Than Meter-Squared: 100 mg/m 2 orally twice daily Patient Selection Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens . An FDA-approved test for the detection of NTRK gene fusion is not currently available.

Contraindications

None. None.

Warnings and precautions

• Neurotoxicity: Advise patients and caretakers of the risk of neurologic adverse reactions. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. ( 2.3 , 5.1 ) • Hepatotoxicity: Monitor liver tests including ALT and AST every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. ( 2.6 , 5.2 ) • Embryo-Fetal Toxicity: Can cause fetal harm.

Pregnancy

Pregnancy Risk Summary Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action , VITRAKVI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on VITRAKVI use in pregnant women.

Storage and supply

Capsules 25 mg: Hard gelatin opaque white capsule size #2 with blue printing of "LOXO" and "LARO 25 mg" on the body of the capsule. • 60 count bottle NDC# 71777-390-01 100 mg: Hard gelatin opaque white capsule size #0 with blue printing of "LOXO" and "LARO 100 mg" on the body of the capsule.

Source: Larotrectinib (Vitrakvi) — US FDA prescribing information, 2018-12-05, DailyMed. Summarised and shortened; the full label governs. Iranian registration, indications and labelling may differ.