CAPETUCA+TRAS

REPEAT EVERY 21 DAYS

Until disease progression or unacceptable toxicity

Treatment with trastuzumab may continue if tucatinib or capecitabine are discontinued due to unacceptable toxicity.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Routine pre-medication is not recommended for trastuzumab.  Refer to the "Management of Infusion-Related Reactions" table on pre-medications at re-challenge.

Other Supportive Care:

• Topical emollients (e.g. hand creams, udder balm) therapy may ameliorate the manifestations of hand-foot syndrome in patients receiving capecitabine.
• Standard antidiarrheal agents (eg. loperamide) should be initiated as medically appropriate, as early as possible.
• Also refer to CCO Antiemetic Recommendations.

Doses should be modified according to the protocol by which the patient is being treated. 

Patients should be tested for DPD deficiency before starting treatment with capecitabine. Refer to the DPD Deficiency Guidance for Clinicians for more information.

In patients with unrecognized DPD deficiency, acute, life-threatening toxicity may occur; if acute grade 2-4 toxicity develops, treatment should be stopped immediately and permanent discontinuation considered based on clinical assessment of the toxicities.

Patients with brain metastases requiring immediate local therapy should undergo local CNS directed therapy prior to being treated with tucatinib, if appropriate.

If trastuzumab and capecitabine are both discontinued, tucatinib must also be discontinued.

Capecitabine

• Do not start treatment with capecitabine unless baseline neutrophil counts are ≥ 1.5 x 10⁹/L and/or platelet counts of ≥ 100 x 10⁹/L.

• Patients should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Supportive care should be provided, including loperamide for diarrhea. 

• Doses should not be re-escalated if reduced for toxicity.

• Missed or omitted doses of capecitabine should not be replaced.

• Dose modifications are mandatory for gastrointestinal, dermatological toxicity and hyperbilirubinemia.  Practitioner may elect not to reduce dose for other toxicities unlikely to become serious or life-threatening.

Non-hematologic Toxicity:
 

Hematologic Toxicity:

Hold capecitabine during a treatment cycle in the presence of grade 3 or 4 hematologic toxicity.

Tucatinib and Trastuzumab

Non-Hematologic Toxicity:

*No dose modifications are required for alopecia
 

Trastuzumab Hematologic Toxicity:

Dosage with myelosuppression: No adjustment required for myelosuppression.

Trastuzumab Cardiotoxicity:

Product Monograph Recommendations

• Trastuzumab should be held with a fall in LVEF (if LVEF falls ≥10 points from baseline and/or if LVEF falls to < 50%). Repeat LVEF in 3 weeks and consider discontinuing. Discontinue if clinically significant cardiac dysfunction or cardiac failure develops.

Canadian Consensus Guidelines

• Discontinue if symptomatic.
   

Management of trastuzumab therapy in adjuvant breast cancer patients with asymptomatic decreases in LVEF (Mackey et al 2008):

_{¹ Consider cardiac assessment and starting ACEI therapy.
² After 2 holds, consider permanent trastuzumab discontinuation.
³ Start ACEI therapy and refer to cardiologist.}

Trastuzumab - Dosage with Other Toxicity:

Management of Infusion-related reactions (trastuzumab):

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

No dose adjustment is required for patients on capecitabine, trastuzumab and tucatinib.  

Capecitabine:

Older patients (≥ 65 years) are more susceptible to the effects of fluoropyrimidine-based therapies with increased grade 3/4 adverse effects, especially when used in combination.

Trastuzumab:

The risk of cardiac dysfunction and myelosuppression may be increased in elderly patients.  The reported trials did not determine differences in efficacy between patients ≥ 65 years versus younger patients.

 

Tucatinib:

No overall differences in effectiveness was observed in patients ≥ 65 years compared to younger patients. Patients ≥ 65 years were more likely to experience a serious adverse event such as diarrhea and vomiting and more likely to discontinue treatment compared to younger patients <65 years.

Refer to capecitabine, tucatinib, trastuzumab drug monograph(s) for additional details of adverse effects

Refer to capecitabine, tucatinib, trastuzumab drug monograph(s) for additional details

• Concomitant administration of capecitabine with sorivudine or analogues is contraindicated, given increased risk of capecitabine toxicity (may be fatal). Wait at least 4 weeks after sorivudine treatment before starting capecitabine.

• Avoid concomitant administration of capecitabine with phenytoin as capecitabine may increase phenytoin levels. Monitor phenytoin levels if co-administered.

• Caution and monitor INR/PT when capecitabine is co-administered with warfarin.

• Caution and monitor for reduced effectiveness of capecitabine when co-administered with proton-pump inhibitors. Consider switching to an antacid if appropriate.

• Avoid concomitant administration of tucatinib and moderate or strong CYP2C8 inducers and strong CYP3A4 inducers.

• Avoid concomitant administration of tucatinib and strong CYP2C8 inhibitors. If co-administration is unavoidable, reduce tucatinib starting dose to 100 mg twice daily and increase monitoring for tucatinib-related toxicity. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume tucatinib at dose taken prior to initiating the inhibitor. If co-administered with a moderate inhibitor, increase monitoring for toxicity.

• Avoid concomitant administration of tucatinib and CYP3A4 substrates.  If co-administration is unavoidable, consider dose modification of CYP3A substrates with narrow therapeutic indices and/or increased monitoring for potential adverse reactions.

• Caution when co-administered tucatinib with P-gp substrates with narrow therapeutic indices. Refer to the prescribing information of sensitive P-gp substrates for dose adjustment recommendations.

• Avoid concomitant administration of trastuzumab with anthracyclines and other cardiotoxic drugs. Use extreme caution with anthracyclines for up to 28 weeks after stopping trastuzumab.

Refer to capecitabine, tucatinib, trastuzumab drug monograph(s) for additional details

Note:  Different trastuzumab products are not interchangeable.
 

Administration: capecitabine

• Oral self-administration; drug available by outpatient prescription.

• Doses are given orally approximately 12 hours apart, within 30 minutes after the end of a meal.

• Swallow tablets whole; do not crush or cut tablets.

• If a capecitabine dose is missed, skip this and give the next dose at the usual time. Missed or omitted doses should not be replaced.

• Store tablets at 15ºC to 30ºC in the original package.

Administration: tucatinib

• Swallow tablets whole, do not chew, crush, or split prior to swallowing.

• Take approximately 12 hours apart at the same time each day with or without a meal.

• Tucatinib and capecitabine may be taken at the same time.

• If a dose is missed or vomited, administer the next dose at its usual time.

• Store original container at a controlled room temperature between 20ºC and 25ºC

• Protect from moisture. 

Administration: trastuzumab

• Different trastuzumab products are NON-INTERCHANAGEABLE.  There have been fatal reports where the incorrect trastuzumab product (e.g. trastuzumab emtansine instead of trastuzumab) was administered to patients with breast cancer in the clinical trials setting.

• DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.

• Mix in 250 mL bag NS. Do not use D5W as it causes protein aggregation. Do not shake.

• Administer loading dose over 90 minutes. Observe during the infusion and for at least 90 minutes after the infusion.

• If no previous IR, subsequent infusions may be administered over 30 minutes. Observe patients during the infusions and for at least 30 minutes after the infusions.

• Should not be mixed or diluted with other drugs.

• Compatible with polyvinylchloride, polyethylene or polypropylene bags.

• Diluent supplied - Bacteriostatic Water for Injection (BWFI) - contains benzyl alcohol 1.1%; if patient is hypersensitive to benzyl alcohol, may reconstitute with Sterile Water for Injection, but must be used immediately and discard unused portion.

• Solution reconstituted with the supplied BWFI is stable up to 28 days refrigerated.

• Do not freeze the reconstituted solution.

• Missed Dose

  • If a dose is missed by 1 week or less, the product monograph recommends the usual maintenance dose (2 mg/kg if on a weekly schedule or 6 mg/kg if on an every-3-week schedule) should be administered as soon as possible (do not wait until the next planned cycle) and subsequent maintenance doses should be administered 7 or 21 days later (based on patient's maintenance dose/schedule)

  • If a dose is missed by >1 week^*, the product monograph recommends a re-loading dose (4 mg/kg if patient receives trastuzumab weekly; 8 mg/kg if on an every-3-week schedule) should be administered (over 90 minutes) as soon as possible, followed by the usual maintenance dose administered 7 or 21 days later (based on patient's maintenance dose/schedule).

    ^*For every 3-week dosing, consider repeating the loading dose for treatment delays ≥ 3 weeks (i.e.≥ 6 weeks from last dose).  [Breast Disease Site Group consensus].

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Contraindications:

• Patients who have a known hypersensitivity to capecitabine, its excipients, 5FU or any ingredient in the formulation or component of the container.

• Patients who are hypersensitive to tucatinib or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

• Patients with known hypersensitivity to trastuzumab, Chinese Hamster Ovary (CHO) cell proteins, or any components of the product.

• Patients with known near or complete absence of DPD (dihydropyrimidine dehydrogenase) activity. Refer to the DPD Deficiency Guidance for Clinicians for more information.

• Concomitant use of capecitabine with sorivudine or related analogues (i.e. brivudine), given potential fatal drug interaction.

• Patients with severe renal impairment (CrCl <30 mL/min).
   

Other Warnings/Precautions:

• Trastuzumab should only be used in patients whose tumours overexpress HER2.

• Use with caution in patients with known chronic liver disease, carriers of hepatitis B or C or with pre-existing liver function test abnormalities (total bilirubin > 1.5 × ULN, or AST/ALT > 2.5 × ULN, or AST/ALT > 5 × ULN if liver metastases were present) as they were excluded from clinical trials.

• Patients with risk factors for dehydration, pre-existing renal dysfunction or on nephrotoxic agents.

• Patients with partial DPD deficiency - use with extreme caution. Refer to the DPD Deficiency Guidance for Clinicians for more information.

• Patients with a history of cardiovascular disease.

• The risk of cardiotoxicity must be weighed against the potential benefits of treatment, especially in older patients, patients with pre-existing cardiac disease (including LVEF < 55%) and patients who have had prior cardiotoxic therapy. Note: in the adjuvant trials, patients with cardiac risk factors were excluded from the trials.

• Exercise caution in patients with pre-existing pulmonary disease or patients with extensive pulmonary tumour involvement, as they may experience more severe lung toxicities.

• Use with caution before or after anthracyclines (for up to 28 weeks after trastuzumab discontinuation due to long half-life).

• Capecitabine contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption

• Patients should exercise caution when driving or operating a vehicle or potentially dangerous machinery.

Pregnancy / Lactation:

• These drugs are not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 7 months after the last dose.

• Breastfeeding is not recommended.

• Fertility effects: 

  • capecitabine: observed in animal studies.

  • tucatinib: documented in animals

  • trastuzumab: no data in humans; animal studies showed no evidence of impaired fertility.

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Outpatient prescription for home administration (capecitabine and tucatinib)

Bartsch R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol 2007;25(25):3853-8.

CADTH reimbursement recommendation (Tucatinib: in combination with trastuzumab-capecitabine for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer), November 2021.

Capecitabine, trastuzumab and tucatinib drug monographs, Ontario Health (Cancer Care Ontario).

Ishida T, Kiba T, Takeda M, et al. Phase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanes. Cancer Chemother Pharmacol 2009;64(2):361-9.

Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 2020; 382:597-609. 

Schaller G, Fuchs I, Gonsch T, et al. Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes. J Clin Oncol. 2007;25(22):3246-50.

Supplementary Appendix to: Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 2020;382:597-609. DOI: 10.1056/NEJMoa1914609.