Larotrectinib

Indications

Larotrectinib is used for: Indicated for treatment of patients with solid tumors that have a neurotrophic tyrosine receptor 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 alternative treatments or have progressed following treatment

Adult Dose

Solid Tumors Indicated for treatment of patients with solid tumors that have a neurotrophic tyrosine receptor 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 alternative treatments or have progressed following treatment 100 mg PO BID Continue until disease progression or until unacceptable toxicity Hepatic impairment Mild (Child-Pugh A): No dosage adjustment necessary Moderate to severe (Child-Pugh B or C): Reduce starting dose by 50%

Child Dose

Solid Tumors Indicated for treatment of patients with solid tumors that have a 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 alternative treatments or have progressed following treatment Body surface area (BSA) <1 m²: 100 mg/m² PO BID BSA >1 m²: 100 mg PO BID Continue until disease progression or until unacceptable toxicity

Renal Dose

Renal impairment Mild to severe: No dosage adjustment necessary

Administration

Capsules or oral solution may be used interchangeably

Contra Indications

Precautions

Neurologic adverse reactions (any grade) occurred; majority of neurologic adverse reactions occurred within first 3 months of treatment; advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions Increased transaminases of any grade occurred; median time to onset of increased AST/ALT was 2 months; monitor liver tests every 2 weeks during first month of treatment, then monthly thereafter, and as clinically indicated Can cause fetal harm when administered to pregnant women

Pregnancy-Lactation

Pregnancy Based on literature reports, findings from animal studies, and its mechanism of action, embryo-fetal harm may occur when administered to a pregnant woman There are no available data on use in pregnant women Verify pregnancy status in females of reproductive potential prior to initiation Animal data Administration of larotrectinib to pregnant rats and rabbits during organogenesis resulted in malformations at maternal exposures were ~11- and 0.7-times (observed at 100 mg PO BID) Contraception Females of reproductive potential: Advise to use of effective contraception during treatment and for at least 1 week after last dose Males: Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after last dose Infertility Based on histopathological findings in reproductive tracts of female rats in a 1-month repeated-dose study, fertility may be reduced Lactation There are no data on presence of larotrectinib or its metabolites in human milk and its effects on the breastfed child or on milk production Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 1 week after final dose

Interactions

Larotrectinib is a substrate of CYP3A4 (major); also a P-gp and BCRP substrate Larotrectinib moderately inhibits CYP3A4 Strong CYP3A4 inhibitors Coadministration with a strong CYP3A4 inhibitor may increase larotrectinib plasma concentrations and potentially result in higher incidence of adverse reactions Avoid use with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice; if coadministration of strong CYP3A4 inhibitors cannot be avoided, modify dose as recommended Strong CYP3A4 inducers Coadministration with a strong CYP3A4 inducer may decrease larotrectinib plasma concentrations, which may decrease efficacy Avoid use with strong CYP3A4 inducers; if coadministration of strong CYP3A4 inducers cannot be avoided, modify dose as recommended Sensitive CYP3A4 substrates Coadministration with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase incidence and/or severity of adverse reactions Avoid use with sensitive CYP3A4 substrates; if coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor for increased adverse reactions of these drugs

Side Effects

Side effects of Larotrectinib : >10% Increased AST/ALT (45%) Anemia (42%) Fatigue (37%) Hypoalbuminemia (35%) Increased alkaline phosphatase (30%) Nausea (29%) Dizziness (28%) Vomiting (26%) Cough (26%) Constipation (23%) Neutropenia (23%) Diarrhea (22%) Pyrexia (18%) Dyspnea (18%) Peripheral edema (15%) Increased weight (15%) Headache (14%) Arthralgia (14%) Myalgia (14%) Muscular weakness (13%) Decreased appetite (13%) Abdominal pain (13%) Back pain (12%) Pain in extremity (12%) Hypertension (11%) 1-10% Nasal congestion (10%) Fall (10%) Anemia, Grade 3 or 4 (10%) Neutropenia, Grade 3 or 4 (7%) Increased weight, Grade 3 or 4 (4%) Fatigue, Grade 3 or 4 (3%) Increased alkaline phosphatase, Grade 3 or 4 (3%) Increased AST/ALT, Grade 3 or 4 (45%) Diarrhea, Grade 3 or 4 (2%) Dyspnea, Grade 3 or 4 (2%) Decreased appetite, Grade 3 or 4 (2%) Hypertension, Grade 3 or 4 (2%) Hypoalbuminemia, Grade 3 or 4 (3%) Pyrexia, Grade 3 or 4 (1%) Nausea, Grade 3 or 4 (1%) Vomiting, Grade 3 or 4 (1%) Arthralgia, Grade 3 or 4 (1%) Myalgia, Grade 3 or 4 (1%) Back pain, Grade 3 or 4 (1%) Pain in extremity, Grade 3 or 4 (1%) Fall, Grade 3 or 4 (1%) Constipation, Grade 3 or 4 (1%) Dizziness, Grade 3 or 4 (1%)

Mode of Action

Highly selective inhibitor of tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC 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 In tumor models, larotrectinib demonstrates antitumor activity in cells by activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK overexpression