Tucatinib (Monograph)

Brand name: Tukysa
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Sep 28, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a highly selective, reversible tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2).

Uses for Tucatinib

Breast Cancer

Used in combination with trastuzumab and capecitabine for the treatment of HER2-positive advanced unresectable or metastatic breast cancer in adults, including those with brain metastases, previously treated with ≥1 anti-HER2-based regimen in the metastatic setting (designated an orphan drug by FDA for this cancer).

Colorectal Cancer

Used in combination with trastuzumab for treatment of adults with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Accelerated approval based on tumor response rate and durability of response; continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Designated an orphan drug by FDA for treatment of HER2-positive colorectal cancer.

Tucatinib Dosage and Administration

General

Pretreatment Screening

Serum ALT, AST, and bilirubin concentrations.
Verify pregnancy status in females of reproductive potential.
In patients with unresectable or metastatic colorectal cancer, confirm presence of specific RAS mutations mutations with an FDA-approved test.
In patients with unresectable or metastatic colorectal cancer, confirm presence of HER2 overexpression or gene amplification with a laboratory assessment of tumor tissue.

Patient Monitoring

Serum ALT, AST, and bilirubin concentrations every 3 weeks during therapy, and as clinically indicated.

Premedication and Prophylaxis

Prophylactic use of antidiarrheal agents not required in principal efficacy study (HER2CLIMB study).

Dispensing and Administration Precautions

Based on the Institute for Safe Medication Practices (ISMP), tucatinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer twice daily, approximately 12 hours apart at the same time each day, without regard to meals.

Swallow tablets intact; do not chew, crush, crack, break, or split.

If a dose of tucatinib is missed or vomited, take the next dose at the regularly scheduled time.

Dosage

Adults

Breast Cancer

Oral

300 mg twice daily in combination with trastuzumab and capecitabine. Continue until disease progression or unacceptable toxicity.

Consult respective manufacturers' labelings or published protocols for information on dosage and method and sequence of administration of other antineoplastic agents used in combination with tucatinib.

May administer capecitabine and tucatinib at the same time. In the HER2CLIMB study, capecitabine 1 g/m² twice daily within 30 minutes after a meal was administered on days 1–14 and trastuzumab 8 mg/kg IV initially, followed by either 6 mg/kg IV or 600 mg by sub-Q injection was administered on day 1 of each 21-day cycle.

Colorectal Cancer

Oral

300 mg twice daily in combination with trastuzumab. Continue until disease progression or unacceptable toxicity.

Dosage Modification for Toxicity

Oral

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of drug may be necessary. When dosage reduction is necessary, reduce dosage as described in Table 1.

Table 1. Dosage Reduction for Tucatinib Toxicity.1
Dose Reduction Level	Recommended Dosage Reductions for Adverse Reactions
First	250 mg twice daily
Second	200 mg twice daily
Third	150 mg twice daily
Fourth	Permanently discontinue tucatinib

If an adverse reaction occurs, modify dosage accordingly (see Table 2).

Table 2: Dosage Modification for Tucatinib Toxicity1
Adverse Reaction and Severity	Modification
Diarrhea (Grade 3 without anti-diarrheal treatment)	Initiate or intensify appropriate medical therapy. Hold tucatinib until recovery to ≤ Grade 1, then resume at the same dose level.
Diarrhea (Grade 3 with anti-diarrheal treatment)	Initiate or intensify appropriate medical therapy. Hold tucatinib until recovery to ≤ Grade 1, then resume at the next lower dose level.
Diarrhea (Grade 4)	Permanently discontinue
Hepatotoxicity (Grade 2 bilirubin [>1.5 to 3 × ULN])	Hold tucatinib until recovery to ≤ Grade 1, then resume at the same dose level.
Hepatotoxicity (Grade 3 ALT or AST [> 5 to 20 × ULN] OR Grade 3 bilirubin [> 3 to 10 × ULN])	Hold tucatinib until recovery to ≤ Grade 1, then resume at the next lower dose level.
Hepatotoxicity (Grade 4 ALT or AST [> 20 × ULN] OR Grade 4 bilirubin [> 10 × ULN])	Permanently discontinue
Hepatotoxicity (ALT or AST > 3 × ULN AND Bilirubin > 2 × ULN)	Permanently discontinue
Other adverse reactions (Grade 3)	Hold tucatinib until recovery to ≤ Grade 1, then resume at the next lower dose level.
Other adverse reactions (Grade 4)	Permanently discontinue

Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes

Avoid concomitant use of tucatinib with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 2C8. If concomitant use cannot be avoided, reduce tucatinib to 100 mg twice daily. If concomitant use of the potent CYP2C8 inhibitor is discontinued, return tucatinib dosage (after 3 elimination half-lives of the CYP2C8 inhibitor) to the dosage used prior to initiation of the CYP2C8 inhibitor.

Special Populations

Hepatic Impairment

Oral

Severe hepatic impairment (Child-Pugh class C): Reduce dosage to 200 mg twice daily.

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.

Renal Impairment

Oral

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute using Cockcroft-Gault formula): No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute using Cockcroft-Gault formula): Combination therapy with tucatinib, capecitabine, and trastuzumab not recommended.

Geriatric Use

No specific dosage recommendations for patients ≥65 years of age.

Cautions for Tucatinib

Contraindications

None.

Warnings/Precautions

Diarrhea

Severe diarrhea associated with dehydration, hypotension, acute kidney injury, and death reported. Median time to initial onset of diarrhea was 12 days. Median time to resolution of diarrhea was 8 days.

Administer antidiarrheal therapy as clinically indicated if diarrhea occurs during therapy. Perform diagnostic tests to exclude other causes of diarrhea. If diarrhea occurs, temporary interruption, dosage reduction, or permanent discontinuance of therapy may be necessary.

Hepatic Toxicity

Severe hepatotoxicity (i.e., elevations in ALT and/or AST concentrations >5 times the ULN, elevations in serum bilirubin concentrations >3 times the ULN) reported.

Monitor liver function tests (i.e., ALT, AST, bilirubin concentrations) prior to initiation of therapy, every 3 weeks thereafter, and as clinically indicated. If hepatotoxicity occurs, temporary interruption, dosage reduction, or permanent discontinuance of therapy may be necessary.

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action and animal findings, tucatinib may cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiating tucatinib therapy in females of reproductive potential. Advise females of reproductive potential and men who are partners of such women to use effective contraception while receiving the drug and for ≥1 week after the last dose of the drug. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Impairment of Fertility

Results of animal studies suggest tucatinib may impair male and female fertility.

Specific Populations

Pregnancy

May cause fetal harm.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiating tucatinib therapy in females of reproductive potential.

Advise females of reproductive potential and men who are partners of such women to use effective contraception while receiving the drug and for ≥1 week after the last dose of the drug. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Lactation

Not known whether tucatinib or its metabolites distribute into milk, affect milk production, or affect breast-fed infants.

Women should not breast-feed during therapy and for ≥7 days after the last dose of the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

In the HER2CLIMB study, 26% of tucatinib-treated patients were ≥65 years of age and 2.5% were ≥75 years of age. No overall difference in efficacy relative to younger adults. Serious adverse reactions (e.g., diarrhea, vomiting, nausea) reported more frequently in geriatric patients.

In the MOUNTAINEER study, 12 patients were ≥65 years of age; however, there were too few patients to assess differences in effectiveness or safety.

Hepatic Impairment

Mild or moderate hepatic impairment: Systemic exposure not substantially altered. No dosage adjustment required.

Severe hepatic impairment: Systemic exposure increased by 1.6-fold. Reduce tucatinib dosage to 200 mg twice daily.

Renal Impairment

Mild or moderate renal impairment: Pharmacokinetics not substantially affected. No dosage adjustment required.

Severe renal impairment: Pharmacokinetics not studied.

Common Adverse Effects

Adverse effects (≥20%) of patients with metastatic breast cancer: Diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, rash.

Adverse effects (≥20%) of patients with unresectable or metastatic colorectal cancer: Diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, pyrexia.

Tucatinib increases S_cr by inhibiting tubular secretion of creatinine. Elevated S_cr concentrations are reversible in most patients following discontinuance of therapy. Use of alternative markers for renal function may be necessary if elevated S_cr concentrations persist.

Drug Interactions

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A.

In vitro, reversible inhibitor of CYP isoenzymes 2C8 and 3A. Time-dependent inhibitor of CYP3A, but does not inhibit CYP isoenzymes 1A2, 2B6, 2C9, 2C19, and 2D6, or uridine diphosphate-glucuronosyltransferase (UGT) 1A1.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, multidrug and toxin extrusion (MATE) 1, MATE2K, or bile salt export pump (BSEP).

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2C8 inhibitors: Possible increased systemic exposure to tucatinib and increased risk of adverse effects. Avoid concomitant use. If concomitant use cannot be avoided, reduce tucatinib dosage to 100 mg twice daily. If concomitant use of potent CYP2C8 inhibitor is discontinued, return tucatinib dosage (after 3 elimination half-lives of the CYP2C8 inhibitor) to dosage used prior to initiation of CYP2C8 inhibitor.

Moderate CYP2C8 inhibitors: Possible increased systemic exposure to tucatinib and increased risk of adverse effects. If used concomitantly, monitor for signs of tucatinib toxicity.

Potent CYP3A or moderate CYP2C8 inducers: Possible decreased systemic exposure to tucatinib and reduced efficacy of tucatinib. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible increased systemic exposure to the CYP3A substrate and increased risk of adverse effects of the substrate drug. Avoid concomitant use with CYP3A substrates that have a narrow therapeutic index. If concomitant use cannot be avoided, reduce dosage of the CYP3A substrate as appropriate.

Drugs Affected by Transport Systems

P-gp substrates: Possible increased systemic exposure of the P-gp substrate and increased risk of adverse effects of the substrate drug. If used concomitantly with a P-gp substrate that has a narrow therapeutic index, reduce dosage of the P-gp substrate as appropriate.

Specific Drugs

Drug	Interaction	Comments
Digoxin	Increased AUC and peak plasma concentrations of digoxin by 1.5- and 2.4-fold, respectively	Avoid concomitant use; if concomitant cannot be avoided, adjust dosage of digoxin as appropriate
Gemfibrozil	Increased AUC and peak plasma concentrations of tucatinib by 3- and 1.6-fold, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of tucatinib to 100 mg twice daily When gemfibrozil is discontinued, return tucatinib dosage (after 3 elimination half-lives of gemfibrozil) to prior dosage
Itraconazole	Increased both AUC and peak plasma concentrations of tucatinib by 1.3-fold.
Metformin	Reduced renal clearance of metformin without any effect on GFR Increased AUC and peak plasma concentration of metformin by 1.4- and 1.1-fold, respectively
Midazolam	Increased AUC and peak plasma concentration of midazolam by 5.7- and 3-fold, respectively
Omeprazole	No clinically important effect on pharmacokinetics of tucatinib
Rifampin	Decreased AUC and peak plasma concentrations of tucatinib by 48 and 37%, respectively	Avoid concomitant use
Tolbutamide	No clinically important effect on pharmacokinetics of tucatinib

Tucatinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration and AUC of tucatinib are dose proportional over an oral dosage range of 50–300 mg.

Peak plasma concentrations attained in a median of 2 hours (range 1–4 hours) following oral administration.

Steady-state concentrations are achieved in approximately 4 days; accumulation based on geometric mean AUC accumulation ratios ranged from 2–2.5-foldy.

Food

Administration of high-fat meal did not substantially affect pharmacokinetics of tucatinib.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): Systemic exposure not substantially altered.

Severe hepatic impairment (Child-Pugh class C): AUC increased by 1.6-fold.

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): Pharmacokinetics not substantially altered.

Severe renal impairment (Cl_cr <30 mL/minute): Pharmacokinetics not studied.

Age, serum albumin concentration (2.5–5.2 g/dL), body weight (41–138 kg), and race (White, Black, or Asian) do not affect pharmacokinetics of tucatinib.

Distribution

Extent

Not known whether tucatinib or its metabolites distribute into milk.

Plasma Protein Binding

97.1%.

Elimination

Metabolism

Metabolized principally by CYP2C8 and, to a lesser extent, by CYP3A.

Elimination Route

Eliminated in feces (86% [16% as unchanged drug]) and urine (4.1%).

Half-life

11.9 hours in patients with metastatic breast cancer and 16.4 hours in patients with metastatic colorectal cancer.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C) in original container to protect from moisture. Replace cap securely each time after opening. Do not discard desiccant. Discard after 3 months of first opening.

Actions

Highly selective and reversible tyrosine kinase inhibitor of HER2.
Inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt) pathways.
In vivo, inhibits cellular proliferation of HER2-expressing tumors.
Increased antitumor activity with combination of tucatinib and trastuzumab compared with either drug alone.
Demonstrates 500-fold greater selectivity for HER2 than for epidermal growth factor receptor (EGFR) , thereby potentially reducing the incidence of adverse effects associated with EGFR inhibition, such as adverse GI and dermatologic effects.

Advice to Patients

Inform patients that tucatinib has been associated with severe diarrhea. Instruct patients on how to manage diarrhea and to inform their healthcare provider immediately if there is any change in bowel patterns.
Inform patients that tucatinib has been associated with severe hepatotoxicity and that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately.
Inform pregnant women and females of reproductive potential of the risk to a fetus. Advise women to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with tucatinib and for at least 1 week after the last dose.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with tucatinib and for at least 1 week after the last dose.
Advise women not to breastfeed during treatment with tucatinib and for at least 1 week after the last dose.
Advise males and females of reproductive potential that tucatinib may impair fertility.
Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Available only from a designated specialty pharmacy. Contact manufacturer for additional information.