Larotrectinib – Uses, Dosage, Side Effects, Interaction

Larotrectinib is a selective inhibitor of neurotrophin receptor kinase (NTRK) that is used in the therapy of solid tumors harboring NTRK gene fusions. Larotrectinib is associated with a high rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent liver injury with jaundice.

Larotrectinib is an orally available, tropomyosin receptor kinase (Trk) inhibitor, with potential antineoplastic activity. Upon administration, larotrectinib binds to Trk, thereby preventing neurotrophin-Trk interaction and Trk activation, which results in both the induction of cellular apoptosis and the inhibition of cell growth in tumors that overexpress Trk. Trk, a receptor tyrosine kinase activated by neurotrophins, is mutated in a variety of cancer cell types and plays an important role in tumor cell growth and survival.

Larotrectinib is an orally administered tropomyosin receptor kinase (Trk) inhibitor with demonstrated antineoplastic activity. Upon administration, larotrectinib binds to Trk, thereby preventing neurotrophin-Trk interaction and Trk activation, which results in both the induction of cellular apoptosis and the inhibition of cell growth in tumors that overexpress Trk. Trk, a receptor tyrosine kinase activated by neurotrophins, is mutated in a variety of cancer cell types and plays an important role in tumor cell growth and survival. Originally discovered by Array BioPharma, the agent was ultimately licensed to Loxo Oncology in 2013. Larotrectinib is another example of innovative new cancer therapy medications that target key, specific genetic biomarker drivers of cancer rather than particular types of tumors.

Larotrectinib Sulfate is the sulfate salt form of larotrectinib, an orally available, tropomyosin receptor kinase (Trk) inhibitor, with potential antineoplastic activity. Upon administration, larotrectinib binds to Trk, thereby preventing neurotrophin-Trk interaction and Trk activation, which results in both the induction of cellular apoptosis and the inhibition of cell growth in tumors that overexpress Trk. Trk, a receptor tyrosine kinase activated by neurotrophins, is mutated in a variety of cancer cell types and plays an important role in tumor cell growth and survival.

Originally discovered by Array BioPharma, the agent was ultimately licensed to Loxo Oncology in 2013. Larotrectinib is another example of an innovative new cancer therapy medication that targets key, specific genetic biomarker drivers of cancer rather than particular types of tumors [rx].

Mechanism of Action

Tropomysoin Receptor Kinases (TRK) like TRKA, TRKB, and TRKC elicit activities that regulate the natural growth, differentiation, and survival of neurons when they interact with endogenous neurotrophin ligands. TRKA, TRKB, and TRKC are themselves encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. It has been discovered that chromosomal rearrangements involving in-frame fusions of these genes with various partners, translocations in the TRK kinase domains, mutations in the TRK ligand-binding site, amplifications of NTRK, or the expression of TRK splice variants can result in constitutively-activated chimeric TRK fusion proteins that can act as oncogenic drivers that promote cell proliferation and survival in tumor cell lines. Subsequently, larotrectinib functions as an inhibitor of TRKs including TRKA, B, and C. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

Indications

  • Larotrectinib is a tyrosine kinase inhibitor that is currently indicated for the treatment of adult and pediatric patients with solid tumors that either a) have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, b) are metastatic or where surgical resection is likely to result in severe morbidity, and c) have no satisfactory alternative treatments or that have progressed following treatment. At the moment, these uses of larotrectinib are only approved under the auspices of an accelerated approval by the US FDA based on the overall response rate and duration of response, and continuation of support for these indications may be contingent upon the verification and description of continued clinical benefit in confirmatory trials.
  • Vitrakvi as monotherapy is indicated for the treatment of adult and pediatric patients with solid tumors 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 who have no satisfactory treatment options,
  • Treatment of malignant neoplasms of the central nervous system
  • Treatment of all conditions included in the category of malignant neoplasms (except central nervous system tumors, hematopoietic and lymphoid tissue neoplasms).
  • Larotrectinib is a selective inhibitor of neurotrophin receptor kinase (NTRK) that is used in the therapy of solid tumors harboring NTRK gene fusions.
  • Larotrectinib is a kinase inhibitor used to treat solid tumors with neurotrophic receptor tyrosine kinase gene fusion, are metastatic, high risk for surgery, or have no alternative treatments.

Use in Cancer

Larotrectinib sulfate is approved to treat:

  • Solid tumors that have an NTRK gene fusion without a drug-resistance mutation in certain TRK proteins. It is used in adults and children whose cancer has metastasized (spread to other parts of the body) or cannot be removed by surgery and has gotten worse after other treatments or cannot be treated with other therapies.

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that larotrectinib sulfate provides a clinical benefit in these patients.

Larotrectinib sulfate is also being studied in the treatment of other types of cancer.

Contraindications

  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • Child-Pugh class B liver impairment
  • Child-Pugh class C liver impairment

Dosage

Strengths: 25 mg; 100 mg; 20 mg/mL

Solid Tumors

Body surface area least 1 m2:

  • 100 mg orally 2 times a day until disease progression or unacceptable toxicity
  • Select patients for treatment with this drug based on the presence of a NTRK gene fusion in tumor specimens.
  • 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
  • Have no satisfactory alternative treatments or that have progressed following treatment

Pediatric Dose for Solid Tumors

28 days and older:

  • Body surface area at least 1 m2: 100 mg orally 2 times a day until disease progression or unacceptable toxicity
  • Body surface area less than 1 m2: 100 mg/m2 orally 2 times a day until disease progression or unacceptable toxicity.
  • Select patients for treatment with this drug based on the presence of a NTRK gene fusion in tumor specimens.
  • 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
  • Have no satisfactory alternative treatments or that have progressed following treatment

Dose Adjustments

Recommended Dose Modifications for Adverse Reactions:
FIRST DOSE REDUCTION:

  • Adult and pediatric patients with body surface area (BSA) of at least 1 m2: Reduce dose to 75 mg orally 2 times a day.
  • Pediatric patients with BSA less than 1 m2: Reduce dose to 75 mg/m2 orally 2 times a day.

SECOND DOSE REDUCTION:

  • Adult and pediatric patients with BSA of at least 1 m2: Reduce dose to 50 mg orally 2 times a day.
  • Pediatric patients with BSA less than 1 m2: Reduce dose to 50 mg/m2 orally 2 times a day.

THIRD DOSE REDUCTION:

  • Adult and pediatric patients with BSA of at least 1 m2: Reduce dose to 100 mg orally once a day.
  • Pediatric patients with BSA less than 1 m2: Reduce dose to 25 mg/m2 orally 2 times a day.
  • Permanently discontinue therapy in patients who are unable to tolerate this drug after 3 dose modifications.

Dose Modifications for Coadministration with Strong CYP450 3A4 Inhibitors:

  • Avoid coadministration of strong CYP450 3A4 inhibitors with this drug
  • If coadministration cannot be avoided, reduce the dose of this drug by 50%
  • After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the dose of this drug taken prior to initiating the CYP450 3A4 inhibitor.

Dose Modifications for Coadministration with Strong CYP450 3A4 Inducers:

  • Avoid the coadministration of strong CYP450 3A4 inducers with this drug.
  • If coadministration cannot be avoided, double the dose of this drug.
  • After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the dose of this drug taken prior to initiating the CYP450 3A4 inducer.

Dosage Modifications for Adverse Reactions:
FOR GRADE 3 OR 4 ADVERSE REACTIONS:

  • Withhold therapy until adverse reaction resolves or improves to baseline or Grade 1.
  • Resume at the next dosage modification if resolution occurs within 4 weeks.
  • Permanently discontinue therapy if an adverse reaction does not resolve within 4 weeks.

Administration advice:

  • This drug may be taken with or without food.
  • The capsule or oral solution may be used interchangeably.
  • Do not make up a missed dose within 6 hours of the next scheduled dose.
  • If vomiting occurs after taking a dose, take the next dose at the scheduled time.
  • Swallow capsules whole with water. Do not chew or crush.
  • Discard any unused oral solution remaining after 90 days of first opening the bottle.
  • Prior to preparing an oral dose for administration, refer to the instructions for use.

Side Effects

The Most Common

  • cough
  • constipation
  • diarrhea
  • nausea
  • vomiting
  • stomach pain
  • headache
  • nasal congestion
  • weight gain
  • muscle weakness
  • rash
  • redness, flaking, scaling, or crusting of the skin
  • dizziness; confusion; problems with concentration, attention, or memory; mood changes; difficulty speaking or understanding speech; or sleep problems
  • hallucinations (seeing things or hearing voices that do not exist)
  • muscle or bone pain, changes in your ability to move around, or bone abnormalities
  • fever, sore throat, chills, difficult or painful urination, or other signs of infection
  • swelling in hands, feet, ankles, or lower legs
  • shortness of breath
  • unusual tiredness or weakness; or pale skin
  • increased thirst; change in the amount or color of urine; dry skin; or fainting
  • loss of appetite; nausea; vomiting; yellowing of the skin or eyes; or pain in the upper right part of the stomach
  • redness, pain, blisters, bleeding, or swelling on the palms of your hands or soles of your feet

More common

  • Being forgetful
  • black, tarry, stools
  • bladder pain
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody or cloudy urine
  • blurred vision
  • chest tightness
  • chills
  • confusion as to time, place, or person
  • cough
  • difficult, burning, or painful urination
  • discouragement
  • dizziness
  • falls
  • fear, nervousness
  • feeling sad or empty
  • fever
  • frequent urge to urinate
  • headache
  • holding false beliefs that cannot be changed by fact
  • irritability
  • lack of appetite
  • loss of interest or pleasure
  • loss of memory
  • lower back or side pain
  • nervousness
  • painful or difficult urination
  • pale skin
  • pounding in the ears
  • problems with memory
  • problems with speech or speaking
  • rapid weight gain
  • seeing, hearing, or feeling things that are not there
  • sleepiness or unusual drowsiness
  • slow or fast heartbeat
  • sore throat
  • tingling of the hands or feet
  • trouble breathing
  • trouble concentrating
  • trouble sleeping
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual excitement, nervousness, or restlessness
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • Back pain
  • constipation
  • decreased appetite
  • difficulty in moving
  • increased weight
  • joint pain or swelling
  • muscle stiffness
  • pain in the arms or legs
  • stuffy nose

Rare

  • Chest pain or discomfort
  • confusion
  • decreased urination
  • diarrhea
  • dry mouth
  • fainting
  • heartburn
  • increase in heart rate
  • increased thirst
  • indigestion
  • irregular heartbeat
  • itching, pain, redness, swelling, tenderness, or warmth on the skin
  • lightheadedness
  • loss of consciousness
  • muscle pain, cramps, or weakness
  • nausea
  • problems with movement or walking
  • rapid, shallow breathing
  • seizures
  • severe stomach pain, cramping, or burning
  • sunken eyes
  • swelling of the face, ankles, or hands
  • vomiting
  • vomiting of material that looks like coffee grounds, severe and continuing
  • wrinkled skin
  • yellow skin or eyes

Drug Interaction

Drug-Food Interactions

  • Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of larotrectinib.
  • Avoid St. John’s Wort. This herb induces CYP3A metabolism and may reduce serum levels of larotrectinib.
  • Take with or without food.

Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

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. Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of larotrectinib or its metabolites in human milk and no data on 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 with larotrectinib and for 1 week after the final dose.

Why is this medication prescribed?

Larotrectinib is used to treat a certain type of solid tumors in adults, children, and infants 4 weeks of age and older that have spread to other parts of the body or cannot be treated successfully with surgery. This medication is used only if there are no other treatments available and the tumors have worsened after receiving other treatments. Larotrectinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that tells the cancer cells to multiply. This may help slow the growth of tumors.

How should this medicine be used?

Larotrectinib comes as a capsule and as an solution (liquid) to take by mouth. It is usually taken with or without food twice daily. Take larotrectinib at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take larotrectinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole with water; do not chew or crush them.

Use an oral syringe (measuring device) to accurately measure and take your dose of larotrectinib solution. Ask your pharmacist for an oral syringe if one is not included with your medication. Do not use a household teaspoon to measure the solution. Replace each oral syringe after using it for 7 days or if it becomes damaged. Follow the manufacturer’s instructions about how to use and clean the oral syringe. Ask your doctor or pharmacist if you if you have any questions.

If you are giving the solution to a child, place the tip of the oral syringe into the child’s mouth against the inside of the cheek. Keep the child in an upright position for a few minutes right after giving a dose of larotrectinib. If the child spits up a dose or you are not sure the entire dose was given, do not give another dose.

If you vomit immediately after taking larotrectinib, do not repeat the dose. Continue your regular dosing schedule.

Your doctor may need to temporarily or permanently stop your treatment or decrease your dose of larotrectinib during your treatment. This depends on how well the medication works for you and the side effects you experience. Be sure to tell your doctor how you are feeling during your treatment with larotrectinib. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking larotrectinib,

  • tell your doctor and pharmacist if you are allergic to larotrectinib, any other medications, or any of the ingredients in larotrectinib capsules or solution. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • The following nonprescription or herbal products may interact with larotrectinib: St. John’s wort. Be sure to let your doctor and pharmacist know that you are taking this medication before you start taking larotrectinib. Do not start this medication while taking larotrectinib without discussing with your healthcare provider.
  • tell your doctor if you have or have ever had conditions that affect the nervous system, bone problems including osteoporosis (a condition in which the bones become thin and weak and break easily) or bone fractures, or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or if you plan on fathering a child. If you are female, you will need to take a pregnancy test before you start treatment and use birth control to prevent pregnancy during your treatment and for 1 week after your final dose. If you are male, you and your female partner should use birth control during your treatment and for 1 week after your final dose. Talk to your doctor about birth control methods that you can use. Larotrectinib may decrease fertility in women. However, you should not assume that you cannot become pregnant. If you or your partner become pregnant, call your doctor immediately. Larotrectinib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed during your treatment and for 1 week after your final dose.
  • you should know that larotrectinib may cause drowsiness, dizziness, or confusion. Do not drive a car or operate machinery until you know how this medication affects you.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is less than 6 hours before your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

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References