Larotrectinib

Larotrectinib is an ATP-competitive, selective inhibitor of the tropomyosin receptor kinase (TRK) family: TRKA, TRKB and TRKC, encoded by NTRK1, NTRK2 and NTRK3. It was designed to avoid activity against off-target kinases.

Mechanism of Action

• Target inhibition: in purified-enzyme assays larotrectinib inhibited TRKA, TRKB and TRKC with IC50 values of 5–11 nM. The only other kinase activity occurred at concentrations about 100-fold higher.
• Oncogenic driver: in-frame fusions of NTRK1, NTRK2 or NTRK3 produced by chromosomal rearrangements create chimeric TRK fusion proteins. These are expressed abnormally and have constant kinase activity, which switches on the pathways for cell proliferation and survival.
• Antitumour activity: in vitro and in vivo tumour models showed activity in cells with constitutive TRK activation from gene fusions, deletion of a protein regulatory domain, or TRK overexpression.
• Resistance: acquired resistance mutations have been seen after progression on TRK inhibitors. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including G595R; TRKC mutations with clinically identified acquired resistance include G623R, G696A and F617L. The causes of primary resistance are not known.

Pharmacokinetics

• Absorption: mean absolute bioavailability 34% (range 32–37%). Peak levels are reached about 1 hour after a capsule dose, and steady state within 8 days, with 1.6-fold accumulation. At 100 mg twice daily, adult steady-state Cmax averaged 914 ng/mL and daily AUC 5,410 ng·h/mL. The oral solution has a similar AUC to the capsules and a 36% higher Cmax. A high-fat, high-calorie meal lowered Cmax by about 35% without changing AUC. Gastric pH-modifying agents are unlikely to affect absorption.
• Distribution: volume of distribution about 48 L; about 70% bound to plasma proteins in vitro, independent of concentration; blood-to-plasma ratio about 0.9.
• Metabolism: mainly by CYP3A4 and CYP3A5. In healthy subjects the main circulating components were unchanged larotrectinib (19%) and an O-linked glucuronide (26%).
• Elimination: half-life about 3 hours. After a radiolabelled dose in healthy subjects, 58% of radioactivity (5% as unchanged drug) was recovered in faeces and 39% (20% unchanged) in urine.
• Special populations: in moderate to severe hepatic impairment the starting dose is reduced; no adjustment is needed for renal impairment, age or mild hepatic impairment.

Larotrectinib is indicated as monotherapy for adult and paediatric patients with solid tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion, who:

• have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and
• have no satisfactory treatment options.

The NTRK gene fusion must be confirmed in a tumour specimen by a validated test before treatment starts.

• Hypersensitivity to larotrectinib or to any of the excipients.

In 361 patients with TRK fusion-positive cancer (37% paediatric; median time on treatment 16.2 months), the most common reactions (20% or more) were increased ALT (36%), increased AST (33%), vomiting (30%), anaemia (28%), constipation (28%), diarrhoea (27%), nausea (24%), fatigue (23%) and dizziness (20%). Most reactions were grade 2 or 3. Grade 4 was the highest grade for decreased neutrophil count (2%) and increased ALT (1%), and, in under 1% each, increased AST, decreased leukocyte count, decreased platelet count, muscular weakness and increased alkaline phosphatase. Grade 3 was the highest grade for anaemia (7%), weight increased (6%) and diarrhoea (4%). Permanent discontinuation because of a reaction occurred in 2% of patients.

Very common (≥1/10): anaemia, neutropenia (decreased neutrophil count), leukopenia (decreased white blood cell count), dizziness, nausea, constipation, vomiting, diarrhoea, myalgia, fatigue, increased ALT, increased AST and weight increased.

Common (≥1/100 to <1/10): thrombocytopenia (decreased platelet count), gait disturbance, paraesthesia, dysgeusia, muscular weakness and increased blood alkaline phosphatase.

Not known: liver injury (including cases with ALT or AST at least 3 times the upper limit of normal and bilirubin at least 2 times the upper limit).

Neurologic reactions (dizziness, gait disturbance, paraesthesia) and liver enzyme increases carry specific warnings (see Special Instructions); most began within the first three months, and most reactions leading to dose reduction occurred in that period.

Larotrectinib is a substrate of CYP3A, P-glycoprotein (P-gp) and BCRP, and is itself a weak CYP3A inhibitor.

• Strong or moderate CYP3A inhibitors and P-gp or BCRP inhibitors (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit): may raise larotrectinib levels. With itraconazole, Cmax rose 2.8-fold and AUC 4.3-fold; a single dose of rifampicin (as a P-gp and BCRP inhibitor) raised Cmax 1.8-fold and AUC 1.7-fold. If a strong CYP3A4 inhibitor is needed, reduce the larotrectinib dose by 50%.
• Strong or moderate CYP3A inducers and strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St John’s wort): may lower larotrectinib levels and should be avoided. Rifampicin for 11 days reduced Cmax by 71% and AUC by 81%. There are no clinical data for a moderate inducer, but lower exposure is expected.
• CYP3A substrates with a narrow therapeutic range (alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus): larotrectinib raised the exposure of an oral CYP3A probe substrate 1.7-fold. Use caution; lower doses of these medicines may be needed.
• CYP2B6 substrates (bupropion, efavirenz): in vitro, larotrectinib induces CYP2B6 and may lower their exposure.
• OATP1B1 substrates (valsartan, statins): in vitro, larotrectinib inhibits OATP1B1, so a rise in their exposure cannot be excluded.
• CYP2C8, CYP2C9 and CYP2C19 substrates (repaglinide, warfarin, tolbutamide, omeprazole): a weak induction of PXR-regulated enzymes in vitro may lower their exposure.
• Hormonal contraceptives: it is unknown whether larotrectinib reduces the effect of systemically acting hormonal contraceptives, so a barrier method should be added.
• Grapefruit: capsules and oral solution must not be taken with grapefruit or grapefruit juice.

Treatment must be started by a physician experienced in the administration of anticancer therapies, after a validated test has confirmed an NTRK gene fusion in a tumour specimen. The capsules and the oral solution have equivalent oral bioavailability and may be used interchangeably. Both can be taken with or without food, but not with grapefruit or grapefruit juice.

Recommended Dose

• Adults: 100 mg twice daily until disease progression or unacceptable toxicity.
• Children: dosing is by body surface area (BSA), 100 mg/m² twice daily with a maximum of 100 mg per dose, until disease progression or unacceptable toxicity.
• Birth to under 3 months: the recommended starting dose is 50 mg/m² twice daily.

Capsules and Oral Solution

• Capsules (25 mg and 100 mg): swallow whole with a glass of water. Because of the bitter taste, do not open, chew or crush them.
• Oral solution (20 mg/mL): given by mouth with a 1 mL or 5 mL oral syringe, or enterally through a nasogastric tube. For doses under 1 mL use the 1 mL syringe and round the volume to the nearest 0.1 mL; for doses of 1 mL or more use the 5 mL syringe and calculate the volume to the nearest 0.2 mL. Do not mix it with feeding formulas given by nasogastric tube, as they could block the tube. See SmPC section 6.6 for instructions for syringes and tubes.

Dose Modifications for Adverse Reactions

• Grade 2 reactions: continued dosing may be appropriate with close monitoring that the toxicity does not worsen.
• Grade 3 or 4 reactions (not liver function abnormalities): withhold until the reaction resolves or improves to baseline or grade 1, and resume at the next dose level if this happens within 4 weeks. If it does not resolve within 4 weeks, stop permanently.
• Dose levels: adults and children with BSA of 1.0 m² or more: 75 mg twice daily, then 50 mg twice daily, then 100 mg once daily. Children aged 3 months or older with BSA below 1.0 m²: 75 mg/m² twice daily, then 50 mg/m² twice daily, then 25 mg/m² twice daily. Children under 3 months: 25 mg/m² twice daily at the first modification (no further levels). A child on 25 mg/m² twice daily stays on that dose even if the BSA increases. Stop permanently if three dose modifications are not tolerated.
• Raised liver tests: for grade 2 ALT or AST (above 3 and up to 5 times the upper limit of normal, ULN), repeat tests frequently until resolved. For grade 3 (above 5 and up to 20 times ULN) or grade 4 (above 20 times ULN) with bilirubin below 2 times ULN, withhold and monitor often; stop permanently if there is no resolution, resume at the next dose level only if the benefit outweighs the risk, and stop permanently if a grade 4 elevation occurs after resuming. For ALT or AST at least 3 times ULN with bilirubin at least 2 times ULN, withhold, monitor often, consider stopping permanently, and if resumed start at the next lower dose; stop permanently if it recurs.

With Strong CYP3A4 Inhibitors

If a strong inhibitor cannot be avoided, reduce the larotrectinib dose by 50%. After the inhibitor has been stopped for 3 to 5 elimination half-lives, resume the previous dose.

Special Populations

• Elderly: no dose adjustment.
• Hepatic impairment: reduce the starting dose by 50% in moderate (Child-Pugh B) to severe (Child-Pugh C) impairment; no adjustment in mild (Child-Pugh A) impairment.
• Renal impairment: no dose adjustment.

Missed or Vomited Dose

Do not take two doses at once to make up for a missed dose; take the next dose at the next scheduled time. If vomiting follows a dose, do not take an extra dose.

Efficacy Across Tumour Types

The benefit of larotrectinib was shown in single-arm trials in a relatively small number of patients whose tumours had NTRK gene fusions, on the basis of overall response rate and duration of response in a limited number of tumour types. The effect may differ by tumour type and by concomitant genetic alterations. It should therefore be used only when there are no treatment options with established clinical benefit, or when these are exhausted.

Neurologic Reactions

Dizziness, gait disturbance and paraesthesia have been reported, mostly within the first three months. Consider withholding, reducing or stopping the dose depending on severity and persistence.

Hepatotoxicity

Increases in ALT, AST, alkaline phosphatase and bilirubin have been seen, most ALT and AST increases within 3 months of starting. Liver function (ALT, AST, ALP and bilirubin) should be checked before the first dose, every 2 weeks during the first month, monthly for the next 6 months, and periodically afterwards; patients with raised transaminases need more frequent testing. Withhold, adjust or stop treatment according to severity.

Inducers of CYP3A4 and P-gp

Avoid strong or moderate CYP3A4 and P-gp inducers because of the risk of reduced exposure.

Contraception, Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: women of childbearing potential should have a pregnancy test before treatment and use highly effective contraception during treatment and for at least one month after the last dose. Women using systemically acting hormonal contraceptives should add a barrier method. Men with a partner of childbearing potential who is not pregnant should use highly effective contraception during treatment and for at least one month after the last dose.
• Pregnancy: there are no data in pregnant women. Animal studies do not indicate direct or indirect harm to reproduction, but foetal harm cannot be excluded from the mechanism of action, so use in pregnancy is best avoided.
• Breastfeeding: it is not known whether larotrectinib or its metabolites pass into human milk, and a risk to the infant cannot be excluded. Stop breastfeeding during treatment and for 3 days after the last dose.
• Fertility: there are no clinical data. No relevant effects on fertility were seen in repeat-dose toxicity studies.

Sodium Benzoate in the Oral Solution

Each mL of oral solution contains 2 mg of sodium benzoate; see the SmPC for the related warning.

Effect on Driving

Larotrectinib has a moderate influence on the ability to drive and use machines. Dizziness and fatigue, mostly grade 1 and 2 in the first 3 months, may affect this. Patients should not drive or use machines until they are reasonably sure that treatment does not affect them adversely.

• Capsules: no special storage conditions. They are supplied in a high-density polyethylene bottle with a child-resistant screw cap; each carton holds one bottle of 56 capsules.
• Oral solution: store in a refrigerator at 2–8 °C. Do not freeze. Keep cold-chain handling during transport and supply. After first opening, keep it in the refrigerator (see Shelf Life).

• Capsules: 4 years.
• Oral solution: 3 years unopened; 10 days after first opening, stored in a refrigerator (2–8 °C).

Prescription only (Rx), started by a physician experienced in the administration of anticancer therapies. Larotrectinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription; the oral solution is delivered under cold-chain conditions at 2–8 °C.