Oncology Overview: Tucatinib for Advanced Unresectable or Metastatic HER2-Positive Breast Cancer


Tucatinib is indicated to treat adults with advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who have already received at least 1 anti-HER2-based regimen in the metastatic setting.

On April 17, 2020, tucatinib (Tukysa; SeaGen) became the first drug approved by the FDA under Project Orbis, an initiative that facilitates international collaboration in reviewing oncology products. The FDA worked with its counterparts in Australia, Canada, Singapore, and Switzerland to review tucatinib, which had been granted priority review, breakthrough therapy, fast track, and orphan drug designations.1

Tucatinib is indicated to treat adults with advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who have already received at least 1 anti-HER2-based regimen in the metastatic setting. It is approved for use in combination with trastuzumab plus capecitabine.2

HER2CLIMB (NCT02614794), a randomized, double-blind, placebo-controlled trial, showed that adding tucatinib to a regimen of trastuzumab and capecitabine increased progression-free survival (PFS) and overall survival by 2.2 and 4.5 months, respectively.

A key secondary endpoint showed that the subgroup of patients with brain metastases experienced a similar improvement in PFS.2 This is an important finding, because 25% to 50% of patients with metastatic HER2-positive breast cancer develop brain metastases.1,3

Mechanism of Action

A tyrosine kinase inhibitor, tucatinib works by inhibiting phosphorylation of HER2 and HER3, thereby decreasing downstream MAPK and AKT signaling and cell proliferation. Tucatinib has been shown to decrease the growth of HER2 expressing tumors in vivo.2

Storage and Handling

Tucatinib is stored at room temperature. Pharmacists should instruct patients to keep tucatinib in its original container, carefully replacing the cap after each use, and retaining the included desiccant. Tablets must be used within 3 months of opening the bottle or discarded.2

Dosage and Administration

The dose of tucatinib is 300 mg orally twice daily. Health care providers can share the following counseling points with patients:2

  • Take tucatinib approximately every 12 hours, with or without food, at the same time each day.
  • If taking tucatinib and capecitabine at the same time, take 30 minutes after a meal.
  • Swallow tucatinib tablets whole without chewing, crushing, or splitting.
  • Do not use broken or cracked tucatinib tablets.
  • Omit vomited or missed doses and resume treatment with the next scheduled dose.

Dose Adjustments

No dose adjustment is needed for patients with mild to moderate renal impairment. There are no studies of tucatinib in patients with severe renal impairment.2

Tucatinib prescribing information provides dose reductions for patients with severe hepatic impairment (200 mg twice daily) and for concomitant use with a strong CYP2C8 inhibitor (100 mg twice daily).2

Adverse events (AEs) grading based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 can guide providers in holding, reducing, and discontinuing tucatinib.2

Providers should hold tucatinib until recovery to less than or equal to grade 1 and then restart at the same dose for:

  • Grade 2 bilirubin (1.5 to 3 x the upper limit of normal [ULN])
  • Grade 3 diarrhea in patients not already taking anti-diarrheal treatment2

Providers should hold tucatinib therapy until patients recover to less than or equal to grade 1 and then restart at the next lower dose level for:2

  • Grade 3 ALT or AST (5 to 20 x ULN)
  • Grade 3 bilirubin (3 to 10 x ULN)
  • Grade 3 diarrhea in patients already taking anti-diarrheal treatment
  • Any other grade 3 AE

Prescribers can decrease tucatinib to 250 mg, 200 mg, and 150 mg, each twice daily, for first, second, and third occurrences of serious AEs necessitating dose reduction. If patients cannot tolerate 150 mg twice daily, prescribers should discontinue tucatinib.2

Providers should also permanently discontinue tucatinib for any of the following:

  • ALT or AST exceeding 3 times ULN AND bilirubin exceeding 2 times ULN
  • Grade 4 ALT or AST (exceeding 20 times ULN)
  • Grade 4 bilirubin (exceeding 10 times ULN)
  • Grade 4 diarrhea, or any other grade 4 AE2


As implied by the dosing guidance above, diarrhea and hepatotoxicity are serious AEs associated with tucatinib therapy, and the prescribing information includes warning sections for both.2

In the HER2CLIMB study, 81% of tucatinib (versus 53% of comparator) patients experienced diarrhea. Twelve and a half percent of tucatinib (versus 9% of comparator) patients experienced Grade 3 or higher diarrhea.2

Hepatotoxicity occurred in 42% of tucatinib (versus 24% of comparator) patients, with 9.2% of tucatinib (versus 3.6% of comparator) patients experiencing Grade 3 or higher AEs.

Other common AEs occurring in more than 20% of tucatinib patients included palmar-plantar erythrodysesthesia (hand-foot syndrome), nausea, fatigue, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.2

Pharmacists and other health care providers should be aware that patients taking tucatinib may experience a persistent elevation in serum creatinine (average increase of 32%). This is because of decreased renal tubular transport of creatinine; glomerular function is not affected. Creatinine levels return to normal with tucatinib discontinuation.2

Pregnancy and Breastfeeding

Animal studies show evidence of embryo-fetal mortality and abnormalities, therefore women who are or may become pregnant should be advised of the risk of fetal harm.

Tucatinib’s prescribing information advises that both male and female patients use effective contraception throughout treatment and for a minimum of 1 week after the last dose. The manufacturer does not recommended breastfeeding during or within a week of discontinuing treatment.2

About the Author

Gabrielle Ruggiero, PharmD, BCPS, is a pharmacist at Johnson Memorial Hospital in Stafford Springs, Connecticut.


  1. FDA approves first new drug under international collaboration, a treatment option for patients with HER2-positive metastatic breast cancer [News release]. FDA. April 17, 2020. Accessed July 19, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-new-drug-under-international-collaboration-treatment-option-patients-her2.
  2. Tukysa. Prescribing information. SeaGen; 2020. Accessed July 19, 2021. https://seagendocs.com/TUKYSA_Full_Ltr_Master.pdf
  3. Murthy R, Loi S, Okines A, Paplomata E, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. New England Journal of Medicine. February 13, 2020. Accessed July 19, 2021. https://www.nejm.org/doi/full/10.1056/nejmoa1914609
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