Tucatinib - Uses, Side Effects, and Dosage

Overview:

Tucatinib is a kinase inhibitor initially developed by Array BioPharma and licensed to Cascadian Therapeutics (a part of Seattle Genetics, Incorporated).

This drug is indicated for treating adult patients with advanced unresectable or metastatic HER2 (human epidermal growth factor receptor 2)-positive breast cancer in combination with Trastuzumab and Capecitabine. This also includes patients with brain metastases, who have previously received one or more anti-HER2-based regimens.

Tucatinib inhibits the tyrosine kinase enzyme of the HER2 gene, thereby inhibiting mutations and malignancy. Cells expressing HER2 experience anti-tumor activity on the administration of Tucatinib.

Tucatinib was approved for use by the United States (US) Food and Drug Administration (FDA) in April 2020, and by the European Medicines Agency (EMA) in February 2021.

The drug is available in the market under the brand name Tukysa™.

Trastuzumab: A monoclonal antibody or targeted cancer drug used in the treatment of breast and stomach cancer, specifically HER2 receptor positive cases.

Capecitabine: An orally-administered chemotherapeutic prodrug used in the treatment of metastatic breast and colorectal cancers, that works by inhibiting DNA synthesis and slowing down tumor tissue growth.

How Does Tucatinib Work?

Certain breast cancers present with mutations in the HER2 gene. Mutations in the tyrosine kinase enzyme present in HER2 can lead to cascade effects and eventually cause malignancies through cell signaling and proliferation. Tucatinib can inhibit tyrosine kinase activity. It inhibits the phosphorylation (attachment of a phosphate group to the molecule or ion) of HER2 and HER3 genes, resulting in changes in cell signaling and proliferation activities.

Uses of Tucatinib:

Tucatinib is indicated for use in advanced HER2-positive breast cancer (unresectable or metastatic) including cases of brain metastasis, in patients who have previously received anti-HER2-based therapy. It is to be administered in combination with Trastuzumab and Capecitabine.

Dosage Restrictions:

• Route of Administration: Oral.

• Available Strengths:

• 50 mg tablet.

• 150 mg tablet.

• Dosage Forms:

• 50 mg Tablets: Round, yellow, film-coated tablets with ‘50’ and ‘TUC’ debossed on opposite sides.

• 150 mg Tablets: Oval, yellow, film-coated tablets with ‘150’ and ‘TUC’ debossed on opposite sides.

The recommended dosage of Tucatinib for HER2-positive breast cancer is 300 mg twice daily in combination with Capecitabine and Trastuzumab. The two daily doses should ideally be 12 hours apart and may be taken with or without a meal. If the daily dose is vomited or missed, the next dose should be taken at the usual time.

Capecitabine should be provided as 1000 mg/m2 orally twice daily, 30 minutes after a meal when given with Tucatinib.

Special Considerations:

Dosage Adjustment-

• Hepatic Impairment: In patients with severe hepatic impairment, the dosage may be reduced to 200 mg orally twice daily.

• Adverse Reactions: In patients with adverse reactions, the dosage may be tapered gradually until a concentration at which adverse events are minimal is reached. The minimum allowed concentration is 150 mg twice daily. If the patient is still unable to handle Tucatinib, it must be discontinued immediately. The recommended dose reductions in order are as follows:

• First Reduction - 250 mg twice daily.

• Second Reduction - 200 mg twice daily.

• Third Reduction - 150 mg twice daily.

• Concomitant Use of CYP2C8 Inhibitors: The use of strong CYP2C8 inhibitors is to be avoided. If this is not possible, then the dosage should be reduced to 100 mg orally twice daily.

Drug Safety Concerns:

Drug safety concerns relating to the use of the drug in specific populations have been addressed as follows:

• Pregnancy: Animal studies coupled with the mechanism of action of Tucatinib are indicative of the possibility of fetal harm if administered to a pregnant woman. Pregnant women should be made aware of this possibility before taking the drug.

• Lactation: No data exists on the presence of Tucatinib in human or animal milk, and it is unknown whether it would affect breastfed children. However, there is always the possibility of serious adverse reactions in a breastfed child. Lactating mothers should avoid taking Tucatinib while breastfeeding, or conversely, avoid breastfeeding while on Tucatinib and for a week after stopping the drug.

• Reproduction: Tucatinib can cause fetal harm and can also impair male and female fertility.

Patients should therefore be advised to do the following:

• Inform their physician if they are pregnant before taking Tucatinib.

• Ensure that contraception is used while on Tucatinib and for a week after the final dose.

• Hepatic Impairment: Patients with severe hepatic impairment may show increased Tucatinib exposure. Dose adjustment is therefore required in these cases. Mild to moderate hepatic impairment does not require dose adjustment.

• Renal Impairment: Patients with severe renal impairment show increased exposure to Capecitabine. The use of Tucatinib in combination with Trastuzumab and Capecitabine is not recommended due to the contraindication of Capecitabine in severe renal impairment.

• Geriatric Population: Available data on the incidence of adverse reactions in patients over 65 years of age is not sufficient to determine the safety and effectiveness of Tucatinib. However, it has been found that the incidence of adverse effects was greater in these patients than in those under 65 years.

• Pediatric Population: The safety and effectiveness profiles for Tucatinib in pediatric patients has not been determined thus far.

Warnings and Contraindications:

Contraindications: No contraindications associated with Tucatinib have been reported yet.

Warnings and Precautions:

• Diarrhea: Tucatinib causes diarrhea in most patients with varying degrees of severity. Patients displaying Grade 3 or Grade 4 severity should either be given a much lower dose or discontinue the medication.

• Embryo-Fetal Toxicity: Tucatinib can cause fetal harm. Pregnant women and women of reproductive age should be advised of the same. Patients should use contraception while taking Tucatinib.

• Hepatotoxicity: Tucatinib can cause hepatotoxicity. The dose must either be interrupted or reduced, or the drug must be discontinued based on the severity of hepatotoxicity. Alanine transaminase (ALT), aspartate aminotransferase (AST), and bilirubin levels should be monitored prior to starting treatment and every three weeks during treatment.

For Patients:

What Is HER2-Positive Breast Cancer?

HER2-positive breast cancer is a type of breast cancer that tests positive for the HER2 protein. HER2 or human epidermal growth factor receptor 2 protein can cause cancer cell growth. This type of breast cancer is usually quite aggressive in comparison to other types. However, drugs such as Tucatinib that are specifically directed at HER2-positive breast cancer are extremely effective and have an excellent prognosis.

What Is Unresectable Cancer?

An unresectable tumor is one that cannot be completely removed through surgery for reasons such as the stage of tumor, the size, and the location.

What Is Metastatic Cancer?

Metastatic cancer is cancer that has spread to parts of the body other than the area or organ initially affected. Metastatic cancer can also be considered advanced or Stage 4 cancer.

How Is Unresectable or Metastatic HER2-Positive Breast Cancer Treated?

Chemotherapy is typically given as a first-line treatment to patients with HER2-positive breast cancer in combination with drugs such as Trastuzumab or Pertuzumab (also HER2-targeted drugs). Taxane chemotherapy is preferred for this first-line treatment. Second-line therapy constitutes the use of the antibody-drug conjugate TDM1. The use of third-line therapy with Tucatinib (a third-generation tyrosine kinase inhibitor) with Neratinib (a second-generation drug) has proven to be as effective as TDM1 therapy. This drug combination has been used with Trastuzumab and Capecitabine to treat advanced, unresectable, metastatic breast cancer with good results.

Taxane Drugs: Drugs that stop cell growth by blocking cell division. Taxanes are the conventional chemotherapeutic treatment option for breast cancer.

TDM1: Ado-trastuzumab emtansine is an antibody-drug conjugate consisting of the monoclonal antibody Trastuzumab and the cytotoxic agent DM1. The two are covalently linked, and the drug combines the antitumor properties of Trastuzumab with the cytotoxic (toxic to cells) properties of DM1.

Why Is Tucatinib Prescribed for Breast Cancer?

Tucatinib is in a class of drugs called kinase inhibitors. It blocks the tyrosine kinase enzyme and thereby blocks the action of the protein that causes cancer cells to multiply. This in turn results in the slowing down or complete stopping of the spread of cancer cells. Tucatinib is prescribed along with Trastuzumab and Capecitabine for patients who have previously received one or more anti-HER2-based regimens.

Facts You Should Know About Tucatinib:

Tucatinib is available in tablet form and comes in two strengths (a 50 mg tablet and a 150 mg tablet). Your doctor will usually start you on the recommended dosage of 300 mg and reduce the dosage only if you are unable to handle the drug because of extreme adverse reactions.

How Should You Take Tucatinib?

• Take Tucatinib twice daily about 12 hours apart as prescribed. Read the prescription and drug literature provided to you carefully and speak to your doctor if you have any concerns.

• The tablets should be swallowed whole. They must not be chewed, split, crushed, or broken in any way.

• You may take Tucatinib with or without food.

• If Tucatinib causes you to vomit, do not take another dose. Wait until it is time for the next dose.

• If you experience side effects, let your doctor know. They may reduce the dose of the drug or completely stop it, depending on the severity of your side effects.

• Do not attempt to stop the drug on your own if you experience side effects. Contact your physician or emergency services immediately.

What Should You Discuss With Your Doctor Before Beginning Tucatinib Therapy?

• Allergies: Make it a point to check the ingredient list of Tucatinib tablets and inform your physician if you are allergic to Tucatinib or any of the other ingredients in the formulation.

• Medical History: Inform your doctor of any concurrent illnesses you may be suffering from, particularly kidney or liver disease.

• Drug History: Give your doctor a complete list of the prescription and non-prescription medications you may be taking, any herbal supplements (particularly St. John’s wort), nutritional supplements, and vitamins.

• Pregnancy: Inform your doctor if you are pregnant or planning a pregnancy any time soon. Tucatinib may harm the fetus. If you get pregnant while on Tucatinib, inform your doctor as soon as you find out. Patients are advised to use contraception while on Tucatinib therapy.

• Lactation: Let your doctor know if you are breastfeeding. Breastfeeding should be avoided when taking Tucatinib and for a week after termination of therapy.

• Fertility: Inform your doctor if you are planning to have children in the future. Tucatinib can reduce fertility in males and females.

Is Tucatinib Safe?

Tucatinib is mostly safe but can cause severe adverse reactions such as diarrhea, hepatotoxicity, and embryo-fetal toxicity. Despite these issues, Tucatinib in combination with Trastuzumab and Capecitabine shows good tolerability in most patients.

Is Tucatinib Effective?

The trio of Tucatinib, Trastuzumab, and Capecitanib have achieved good efficacy in the progression-free survival of patients, and in reducing the risk of death. This particular drug therapy is a good option for those who have already undergone treatment with TDM1.

What Side Effects Can You Expect With Tucatinib?

The side effects you can expect from Tucatinib include the following:

• Diarrhea.

• Nausea.

• Vomiting.

• Fatigue.

• Headache.

• Abdominal pain.

• Rashes.

• Decreased appetite.

• Hepatotoxicity: Liver toxicity.

• Palmar-Plantar Erythrodysesthesia: Also called hand-foot syndrome, this is a side effect of some chemotherapeutic drugs that is characterized by blistering, swelling, and redness of the palms and soles of the hands and feet respectively.

• Stomatitis: Inflammation or painful swelling, and soreness of the mouth.

• Anemia: A condition where the blood lacks sufficient healthy red blood cells.

Can You Stop Taking Tucatinib Without Your Doctor’s Approval?

Never stop taking Tucatinib without your doctor’s approval. If you experience side effects, consult the physician or local emergency services and follow the instructions you are given. Your physician can either prescribe an alternative regimen or lower the drug dosage in case of severe side effects.

Are There Any Dietary Restrictions to Consider When Taking Tucatinib?

There are no dietary restrictions with Tucatinib, but if you require special nutritional considerations, you can talk to your doctor about this. You may take Tucatinib with or without food.

How Should You Store Tucatinib?

• Store this medication in its original packaging or container with the lid tightly closed.

• Store Tucatinib at room temperature and not in conditions of heat or moisture.

• Keep the container away from children and pets.

How Should You Dispose of Tucatinib?

• Unused tablets should be disposed of three months after the bottle was opened.

• This drug should not be flushed or disposed of with regular garbage.

• Ideally, get in touch with your local medicine take-back program and dispose of Tucatinib in this way. You can get details from your local pharmacist or recycling department.

• If a medicine take-back program is not available in your locality, find out from your pharmacist or physician about other options available to you.

What To Do in Case of Overdose?

• In case of overdose, call the local poison control helpline or emergency services and visit the hospital as soon as possible.

• If the patient collapses, has a seizure, or difficulty breathing, the family members or others must immediately take them to the emergency room or call emergency services.

For Doctors:

Indications:

Tucatinib is indicated for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, in combination with Trastuzumab and Capecitabine. Patients with brain metastasis may also be included. Patients should have received prior therapy with an anti-HER2-based regimen.

Pharmacology:

• Description:

Tucatinib is a kinase inhibitor with the molecular formula C26H24N8O2 and a molecular weight of 480.52 g/mol.

• Components:

• Tablet Core:

• Copovidone.

• Crospovidone.

• Sodium chloride.

• Potassium chloride.

• Sodium bicarbonate.

• Colloidal silicon dioxide.

• Magnesium stearate.

• Microcrystalline cellulose.

Tucatinib 50 mg Tablet:

• 10.10 mg (0.258 mEq) potassium.

• 9.21 mg (0.401 mEq) sodium.

Tucatinib 150 mg Tablet:

• 30.29 mg (0.775 mEq) potassium.

• 27.64 mg (1.202 mEq) sodium.

• Coating:

Yellow Film Coat:

• Polyvinyl alcohol.

• Titanium dioxide.

• Macrogol/polyethylene glycol.

• Talc.

• Yellow iron oxide (non-irradiated).

Clinical Pharmacology:

• Mechanism of Action:

Tucatinib inhibits tyrosine kinase enzyme in HER2. It does so by inhibiting the phosphorylation of HER2 and HER3, thereby inhibiting the downstream signaling and cell proliferation of MAPK (mitogen-activated protein kinase) and AKT (protein kinase B). Tucatinib also shows anti-tumor properties in tumor cells that express HER2.

• Pharmacodynamics:

• Exposure Response Relationships - Not completely characterized.

• Cardiac Electrophysiology - QTc (corrected QT interval) does not display a large mean increase after treatment with Tucatinib 300 mg twice daily.

[QTc: The corrected QT interval provides a correct adjustment of the QT interval for extremes in the heart rate].

• Pharmacokinetics:

• AUC0-INF- Proportional increase over a dosage range from 50 mg to 300 mg.

• Cmax- Proportional increase over a dosage range from 50 mg to 300 mg.

• Time to Steady State- Four days.

[AUC0-INF: Area under the curve from the time of administration of the drug (0) to the time the drug is no longer present in the body of the patient (infinity)]

[Cmax: Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose.]

• Absorption:

Median time to peak plasma concentration is 2 hours (1 to 4 hour range).

• Effects of Food:

Not clinically meaningful. A single oral dose of Tucatinib after a high-fat meal resulted in the following:

• Increased mean AUC0-INF (1.5-fold).

• Change in Tmax from 1.5 to 4 hours.

• Cmax remained the same.

• Distribution:

• Geometric Mean (CV %) Apparent Volume of Distribution of Tucatinib- 1670 L (66 %).

• Plasma Protein Binding- 97.1%.

• Elimination:

• Geometric Mean (CV %) Half-life of Tucatinib- 8.5 (21 %) hours.

• Apparent Clearance- 148 L/h (55 %).

• Metabolism:

• Primary Metabolism- CYP2C8.

• Others- CYP3A.

• Excretion:

Radiolabeled Tucatinib single oral dose (300 mg) was excreted in the following manner:

• 86% recovered in feces (16% unchanged Tucatinib).

• 4.1% recovered from urine.

• 76% plasma radioactivity remained unchanged, while 19% resulted from identified metabolites, and 5% was unassigned.

Special Considerations:

• Hepatic Impairment - The AUC0-INF of Tucatinib increased 1.6 fold in patients with severe hepatic impairment, while mild to moderate hepatic impairment showed no clinically relevant changes in exposure.

• Renal Impairment - Mild to moderate renal impairment does not impact Tucatinib pharmacokinetics, while the effects of severe renal impairment are unknown.

Drug Interactions:

In Vitro Data:

Tucatinib is a reversible inhibitor of:

• CYP2C8.

• CYP3A.

Tucatinib is a time-dependent inhibitor of:

• CYP3A.

Tucatinib is not an inhibitor of:

• CYP1A2.

• CYP2B6.

• CYP2C9.

• CYP2C19.

• CYP2D6.

• UGT1A1.

Tucatinib is a substrate of:

• P-gp.

• BCRP.

Tucatinib is not a substrate of:

• OAT1.

• OAT3.

• OCT1.

• OCT2.

• OATP1B1.

• OATP1B3.

• MATE1.

• MATE2-K.

• BSEP.

Clinical Trials:

• Study Description: The HER2CLIMB trial evaluated the efficacy and safety of Tucatinib in patients with HER2-positive breast cancer who had been previously treated with an anti-HER2-based regimen and either did or did not have brain metastasis.

• Study Design:

• Type of Study: Randomized, double-blinded, placebo-controlled trial.

• Methods: HER2-positive breast cancer patients (n=612) above 18 years of age were randomized (2:1) into the following groups:

• Tucatinib-combination group (Tucatinib 300 mg orally twice daily in combination with Trastuzumab and Capecitabine).

• Placebo-combination group (Placebo orally twice daily in combination with Trastuzumab and Capecitabine).

• Primary Outcome Measures: Progression-free survival (PFS) among the first 480 patients who underwent randomization.

• Secondary Outcome Measures:

• Overall survival.

• Progression-free survival of patients with brain metastasis.

• Objective response rate.

• Safety.

• Results:

At Year 2:

• Primary Endpoint:

• Overall Survival (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P=0.005): 44.9% in the Tucatinib-combination group and 26.6% in the placebo-combination group.

• Median Overall Survival: 21.9 months in the Tucatinib-combination group and 17.4 months in the placebo-combination group.

• Secondary Endpoint:

• Progression-free survival at 1 year among patients with brain metastases was 24.9% in the Tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001).

• Median progression-free survival was 7.6 months in the Tucatinib-combination group and 5.4 months in the placebo-combination group.

• Adverse Events Profile (Tucatinib Group):

• Diarrhea.

• Nausea.

• Vomiting.

• Fatigue.

• Palmar–plantar erythrodysesthesia syndrome.

Patient Counseling Information:

Administration Instructions:

• Take Tucatinib only as prescribed by the doctor.

• Tucatinib may be taken with or without food.

• Swallow the tablets whole and do not crush, chew, or split them.

Complications/Side Effects:

• Diarrhea: Inform patients of the possibility of severe diarrhea and how to manage it. Patients must be advised to report bowel movement changes to the physician immediately.

• Hepatotoxicity: Patients must be warned of the possibility of hepatotoxicity and trained to recognize the signs and symptoms of liver dysfunction, which they must report to the doctor immediately.

• Infertility: Inform males and females of reproductive potential of the potential for infertility with Tucatinib.

• Pregnancy: Pregnant women and females of childbearing age and potential should be warned of the possibility of embryo-fetal toxicity and should be advised to inform their doctors of pregnancy. They must also be encouraged to use contraception while on Tucatinib therapy.

Lactation: Women must be advised not to breastfeed during treatment with Tucatinib and for a week after the final dose.