Tucatinib

Tucatinib is a reversible, potent and selective inhibitor of the HER2 tyrosine kinase. HER2 is a growth-factor receptor that is overexpressed or amplified in HER2-positive breast cancer, where its kinase activity drives the signals that make tumour cells divide and survive. Blocking that activity slows the growth of HER2-driven tumours. Tucatinib is used together with trastuzumab, an antibody against HER2, and capecitabine, a chemotherapy medicine.

Mechanism of Action

• HER2 inhibition: tucatinib binds reversibly to the HER2 tyrosine kinase. In cell-based signalling assays it is more than 1,000-fold more selective for HER2 than for the epidermal growth factor receptor (EGFR).
• Downstream signalling: in vitro it inhibits phosphorylation of HER2 and HER3, which reduces downstream signalling (including the MAPK and AKT pathways) and cell proliferation, and it induces death of HER2-driven tumour cells.
• In vivo activity: it inhibits the growth of HER2-driven tumours in animal models.
• Combination with trastuzumab: the combination of tucatinib and trastuzumab showed enhanced anti-tumour activity in vitro and in vivo compared with either medicine alone.
• Cardiac electrophysiology: multiple doses of 300 mg twice daily had no effect on the QTc interval in a thorough QT study in healthy subjects.

Pharmacokinetics

• Absorption: after a single 300 mg dose the median time to peak plasma concentration is about 2 hours (range 1–4 hours). Exposure rises in proportion to dose between 50 and 300 mg. With 300 mg twice daily, AUC accumulates 1.7-fold and Cmax 1.5-fold, and steady state is reached in about 4 days. A high-fat meal delayed the peak (from 1.5 to 4 hours) and raised AUC 1.5-fold without changing Cmax; this was not clinically meaningful, so the tablets can be taken with or without food.
• Distribution: apparent volume of distribution about 1,670 L; plasma protein binding about 97% at clinically relevant concentrations. Tucatinib crosses the blood–brain barrier, and the main efficacy study (HER2CLIMB) enrolled patients with or without brain metastases.
• Metabolism: mainly by CYP2C8, and to a lesser extent by CYP3A and aldehyde oxidase. Tucatinib is a substrate of P-gp and BCRP. It is a reversible inhibitor of CYP2C8, a time-dependent (strong) inhibitor of CYP3A, and an inhibitor of the renal transporters MATE1, MATE2-K and OCT2.
• Elimination: geometric mean half-life about 8.5 hours and apparent clearance 148 L/h after a single 300 mg dose in healthy subjects. Elimination is predominantly hepatobiliary and not appreciably renal: in a radiolabelled study about 86% of the dose was recovered in faeces (about 16% of that as unchanged tucatinib) and 4.1% in urine.
• Special populations: no dose adjustment is needed for age 65 or over (not studied above 80 years) or for mild, moderate or severe renal impairment, nor for mild or moderate hepatic impairment; in severe hepatic impairment (Child-Pugh C) a lower starting dose is recommended (see Administration and Dosage).

Tucatinib is used only in combination with trastuzumab and capecitabine.

• HER2-positive breast cancer: adults with HER2-positive locally advanced or metastatic breast cancer who have received at least 2 prior anti-HER2 treatment regimens, in combination with trastuzumab and capecitabine.
• Tumour status: the indication applies to HER2-positive tumours; in the main efficacy study, HER2 overexpression or amplification was confirmed by central laboratory analysis.

• Hypersensitivity to tucatinib or to any of the excipients.

The safety data come from 431 patients with locally advanced unresectable or metastatic HER2-positive breast cancer who received tucatinib with trastuzumab and capecitabine in two studies (HER2CLIMB and ONT-380-005; median exposure 7.4 months). The most frequent grade 3 and 4 reactions (5% or more) were diarrhoea (13%), raised ALT (6%) and raised AST (5%).

Very common (≥1/10): epistaxis; diarrhoea, nausea, vomiting, stomatitis (a grouped term that includes oropharyngeal pain, mouth ulceration and oral pain); rash (a grouped term that includes maculo-papular and acneiform rash, erythema, urticaria, palmar and plantar erythema and skin toxicity); arthralgia; increased AST, increased ALT, increased blood bilirubin, weight decrease.

The SmPC table lists only very common reactions for tucatinib.

Serious adverse reactions occurred in 29% of patients (diarrhoea 4%, vomiting 3%, nausea 2%). Adverse reactions led to dose reduction in 23% of patients (diarrhoea 6%, raised ALT 5%, raised AST 4%) and to discontinuation in 6% (diarrhoea 1%, raised ALT 1%).

• Diarrhoea: occurred in 82% of patients and was grade 3 or higher in 13%. Two patients with grade 4 diarrhoea later died, and diarrhoea contributed to the deaths. The median time to onset was 12 days; 81% of events resolved, after a median of 8 days. Preventive antidiarrhoeal treatment was not required in the study.
• Liver tests: increases in ALT, AST or bilirubin occurred in 41% of patients (grade 3 or higher in 9%), led to dose reduction in 9% and to discontinuation in 1.5%. The median time to onset was 37 days; 84% of events resolved, after a median of 22 days.
• Serum creatinine: rises by about 30% on average within the first cycle because tucatinib blocks the tubular secretion of creatinine. The rise stays stable during treatment and reverses after stopping, with no effect on glomerular function.
• Older patients: serious adverse reactions occurred in 34% of the 82 patients aged 65 or over, against 28% in younger patients; too few patients were 75 or over (8) to judge differences.

Tucatinib is metabolised mainly by CYP2C8 and is a substrate of P-glycoprotein (P-gp). It is also a strong inhibitor of CYP3A and an inhibitor of the renal transporters that handle metformin and creatinine. Trastuzumab and capecitabine have their own interactions, described in their SmPCs.

• Strong CYP3A inducers and moderate CYP2C8 inducers (rifampicin, phenytoin, St John’s wort, carbamazepine): rifampicin halved tucatinib exposure (AUC 0.5-fold, Cmax 0.6-fold). Avoid the combination, as tucatinib may lose activity.
• Strong CYP2C8 inhibitors (gemfibrozil): gemfibrozil raised tucatinib AUC 3.0-fold and Cmax 1.6-fold. Avoid the combination; if it cannot be avoided, the tucatinib dose is reduced (see Administration and Dosage). For moderate CYP2C8 inhibitors there are no clinical data, so monitor more closely for tucatinib toxicity.
• Strong CYP3A inhibitors (itraconazole): tucatinib exposure rose only 1.3-fold; no dose adjustment is needed.
• Proton pump inhibitors (omeprazole): no interaction; no dose adjustment.
• Sensitive CYP3A substrates: tucatinib raised midazolam exposure 3.0-fold (Cmax) and 5.7-fold (AUC). The SmPC names alfentanil, avanafil, buspirone, darifenacin, darunavir, ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam and vardenafil as medicines whose exposure may increase. Avoid the combination where small changes in concentration could cause serious or life-threatening toxicity; otherwise reduce the dose of the CYP3A substrate as its own SmPC advises.
• P-gp substrates: digoxin exposure rose 2.4-fold (Cmax) and 1.5-fold (AUC). Consider reducing the dose of P-gp substrates, including sensitive intestinal substrates such as dabigatran, as their own SmPC advises, and use them with caution where small changes in concentration could cause serious or life-threatening toxicity.
• CYP2C8 substrates: repaglinide exposure rose 1.7-fold; no dose adjustment.
• MATE1/MATE2-K substrates: metformin exposure rose 1.1-fold (Cmax) and 1.4-fold (AUC) because tucatinib reduces its renal clearance without affecting the glomerular filtration rate; no dose adjustment.
• CYP2C9 substrates: no interaction with tolbutamide; no dose adjustment.
• Creatinine: tucatinib blocks the tubular secretion of creatinine, so serum creatinine rises without kidney damage (see Special Instructions).
• Food: tucatinib can be taken with or without food.

Treatment should be started and supervised by a physician experienced in the use of anti-cancer medicinal products. The tablets are swallowed whole, with or without a meal, about 12 hours apart and at the same time every day; they must not be chewed, crushed or split. They may be taken at the same time as capecitabine, and the three medicines can be given in any order.

Recommended Dose

• Tucatinib: 300 mg (two 150 mg tablets) twice daily, continuously, with or without a meal.
• Capecitabine: 1,000 mg/m² orally twice daily on days 1 to 14 of every 21-day cycle, within 30 minutes after a meal.
• Trastuzumab: either intravenously (8 mg/kg on day 1, then 6 mg/kg every 21 days) or subcutaneously (600 mg every 21 days).
• Tucatinib continues until disease progression or unacceptable toxicity. The SmPCs of trastuzumab and capecitabine give further information and the dose modifications for toxicities caused by those medicines.

Dose Reductions

• Starting dose 300 mg twice daily; first reduction 250 mg twice daily; second reduction 200 mg twice daily; third reduction 150 mg twice daily.
• Tucatinib is stopped permanently in patients who cannot tolerate 150 mg twice daily.
• Reduced doses are made up from the 150 mg and 50 mg tablets.

Dose Modifications for Adverse Reactions

Severity is graded by the NCI Common Terminology Criteria for Adverse Events, version 4.03.

• Diarrhoea
  • Grade 1 or 2: no dose modification.
  • Grade 3 without antidiarrhoeal treatment: start or intensify appropriate medical therapy, interrupt tucatinib until recovery to grade 1 or below, then resume at the same dose.
  • Grade 3 with antidiarrhoeal treatment: start or intensify appropriate medical therapy, interrupt until recovery to grade 1 or below, then resume at the next lower dose level.
  • Grade 4: stop tucatinib permanently.
• Raised ALT, AST or total bilirubin
  • Grade 1 bilirubin (above the upper limit of normal, ULN, up to 1.5 × ULN): no dose modification.
  • Grade 2 bilirubin (above 1.5 up to 3 × ULN): interrupt until recovery to grade 1 or below, then resume at the same dose.
  • Grade 3 ALT or AST (above 5 up to 20 × ULN) or grade 3 bilirubin (above 3 up to 10 × ULN): interrupt until recovery to grade 1 or below, then resume at the next lower dose level.
  • Grade 4 ALT or AST (above 20 × ULN) or grade 4 bilirubin (above 10 × ULN): stop permanently.
  • ALT or AST above 3 × ULN together with bilirubin above 2 × ULN: stop permanently.
• Other adverse reactions: grade 1 or 2, no dose modification; grade 3, interrupt until recovery to grade 1 or below, then resume at the next lower dose level; grade 4, stop permanently.

With Strong CYP2C8 Inhibitors

Avoid strong CYP2C8 inhibitors. If one cannot be avoided, reduce the tucatinib starting dose to 100 mg twice daily. After the inhibitor has been stopped for 3 elimination half-lives, resume the dose taken before the inhibitor was started. With moderate CYP2C8 inhibitors, monitoring for tucatinib toxicity is increased.

Special Populations

• Elderly: no dose adjustment at 65 years or over; tucatinib has not been investigated above 80 years.
• Renal impairment: no dose adjustment in mild, moderate or severe impairment.
• Hepatic impairment: no dose adjustment in mild or moderate impairment; in severe impairment (Child-Pugh C) the recommended starting dose is 200 mg twice daily.
• Children and adolescents: safety and efficacy have not been established; no data are available.

Missed Dose

If a dose is missed, the patient takes the next dose at the regularly scheduled time.

Liver Function

Increases in ALT, AST and bilirubin have been reported. ALT, AST and total bilirubin should be monitored every three weeks or as clinically indicated, and treatment is interrupted, reduced or stopped according to severity.

Diarrhoea

Diarrhoea can be severe; dehydration, hypotension, acute kidney injury and death have been reported. Antidiarrhoeal medicines should be given as clinically indicated, and treatment is interrupted, reduced or stopped for grade 3 or higher diarrhoea. Prompt medical management is needed if grade 2 diarrhoea persists together with grade 2 or higher nausea and/or vomiting. Tests to exclude an infectious cause should be done for grade 3 or 4 diarrhoea, and for diarrhoea of any grade with complicating features (dehydration, fever, neutropenia).

Creatinine Increase Without Kidney Damage

Serum creatinine rises by about 30% on average because tucatinib blocks the tubular transport of creatinine, without affecting glomerular function. If it is unclear whether kidney function is impaired, markers that do not rely on creatinine, such as blood urea nitrogen, cystatin C or a calculated glomerular filtration rate that is not based on creatinine, may be considered.

Embryo-Foetal Toxicity

Based on animal findings and its mechanism of action, tucatinib may harm the foetus. In pregnant rabbits it caused foetal abnormalities at maternal exposures similar to the clinical exposure at the recommended dose.

Medicines That Interact

Tucatinib is a strong CYP3A inhibitor, so the SmPC of any other medicine given with it should be checked for advice on CYP3A inhibitors. Strong CYP3A inducers, moderate CYP2C8 inducers and strong CYP2C8 inhibitors should be avoided (see Drug Interactions).

Pregnancy, Breastfeeding and Fertility

• Pregnancy test: the pregnancy status of women of childbearing potential should be verified before treatment starts.
• Contraception: women of childbearing potential should avoid becoming pregnant and use effective contraception during treatment and for at least 1 week after the last dose. Male patients with female partners of childbearing potential should also use effective contraception during that time.
• Pregnancy: there are no data in pregnant women, and animal studies showed reproductive toxicity. Tucatinib should not be used during pregnancy unless the woman’s clinical condition requires it. If a patient becomes pregnant during treatment, the potential hazard to the foetus must be explained to her.
• Breastfeeding: it is unknown whether tucatinib or its metabolites pass into human milk, and a risk to the newborn or infant cannot be excluded. Breastfeeding should be stopped during treatment and may be resumed 1 week after treatment.
• Fertility: no fertility studies have been done; animal findings suggest tucatinib may impair fertility in females of reproductive potential.
• Trastuzumab and capecitabine have their own pregnancy and breastfeeding recommendations in their SmPCs.

Sodium and Potassium

Each 300 mg dose contains 55.3 mg of sodium (about 2.75% of the recommended maximum daily dietary intake for an adult) and 60.6 mg of potassium. The potassium content should be taken into account in patients with impaired kidney function or on a controlled low-potassium diet.

Effect on Driving

Tucatinib has no or negligible influence on the ability to drive and use machines. The patient’s clinical status should be considered when assessing the ability to perform tasks that require judgement, motor or cognitive skills.

Tukysa tablets do not require any special storage conditions. They are supplied in OPA/ALU/PVC blisters sealed with aluminium foil: 50 mg tablets in cartons of 88 (11 blisters of 8) and 150 mg tablets in cartons of 84 (21 blisters of 4); not all pack sizes may be marketed. As with all medicines, keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on restricted medical prescription (Annex II B) from a physician experienced in the use of anti-cancer medicinal products. Tucatinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.