Gabrielle Ruggiero, PharmD, BCPS

On April 17, 2020, tucatinib (Tukysa; SeaGen) became the 

 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.

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.

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.

 This is an important finding, because 25% to 50% of patients with metastatic HER2-positive breast cancer develop brain metastases.

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 

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.

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

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.

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.

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).

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.

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 treatment

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:

Grade 3 diarrhea in patients already taking anti-diarrheal treatment

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.

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 AE

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.

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.

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.

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.

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.

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

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

Tukysa. Prescribing information. SeaGen; 2020. Accessed July 19, 2021. 

https://seagendocs.com/TUKYSA_Full_Ltr_Master.pdf

Murthy R, Loi S, Okines A, Paplomata E, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.

. February 13, 2020. Accessed July 19, 2021. 

https://www.nejm.org/doi/full/10.1056/nejmoa1914609

Articles

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.

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

Human epidermal growth factor receptor 2 (HER2) overexpression occurs in about one-fifth of breast cancers, and pertuzumab plus trastuzumab with chemotherapy is a standard treatment for this condition.

 Approved by the FDA on June 29, 2020, pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo; Genentech) combines these anti-HER2 therapies into a single, subcutaneous injection, offering several advantages.

The pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy requires just 5 to 8 minutes for administration, versus 1 to 2.5 hours for intravenous (IV) pertuzumab plus trastuzumab infusions.

 Once patients have completed their concomitant chemotherapy, the combination therapy eliminates the need for IV access and offers the possibility of home administration.

Additionally, preparation of the pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy is simple, with no reconstitution, dilution, or weight-based dose adjustments required.

 A crossover study found that 85% of patients preferred the combination therapy to IV pertuzumab plus trastuzumab, mainly due to its shorter administration time.

The pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy plus chemotherapy is indicated for:

Neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early stage breast cancer

Adjuvant treatment of high-risk HER2-positive early breast cancer

Treatment of HER2-positive metastatic breast cancer in patients without prior anti-HER2 therapy or chemotherapy for metastatic disease

The FDA approved the pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy based on the phase 3, randomized, open-label, non-inferiority FeDeriCa trial, which enrolled 500 participants with HER2-positive early breast cancer.

During the trial, patients received neoadjuvant pertuzumab, trastuzumab, and hyaluronidase-zzxf or IV pertuzumab plus trastuzumab with chemotherapy. After surgery, patients continued the same anti-HER2 therapy in the adjuvant setting.

The results from the FeDeriCa trial demonstrated:

Non-inferiority of pertuzumab, trastuzumab, and hyaluronidase-zzxf-treated patients’ pertuzumab Cycle 7 serum troughs

Pathological complete response (absence of invasive neoplastic cells in the breast or axillary lymph nodes) in 59.7% and 59.5% of pertuzumab, trastuzumab, and hyaluronidase-zzxf-treated and IV pertuzumab plus trastuzumab-treated patients, respectively

Similar safety profiles for pertuzumab, trastuzumab, and hyaluronidase-zzxf and IV pertuzumab plus trastuzumab (except for injection site reactions due to the subcutaneous administration of pertuzumab, trastuzumab, and hyaluronidase-zzxf)

Pertuzumab binds to subdomain II of HER2, ultimately inhibiting the mitogen-activated protein (MAP) kinase and the phosphoinositide 3-kinase (PI3K) signaling pathways, which then arrests cell growth and promotes apoptosis. On the other hand, trastuzumab binds to subdomain IV of HER2, inhibiting both HER2-mediated cell proliferation and the PI3K signaling pathway.

Pertuzumab and trastuzumab also both show antibody-dependent cell-mediated cytotoxicity against HER2-overexpressing cancer cells. Since hyaluronidase is an enzyme, its addition to pertuzumab and trastuzumab adds to the mechanism of action by increasing the permeability of subcutaneous tissue.

There are 2 pertuzumab, trastuzumab, and hyaluronidase-zzxf doses, each supplied in a single dose vial:

A 15 mL loading dose containing 1200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase. This dose is given at the start of pertuzumab, trastuzumab, and hyaluronidase-zzxf therapy, and if 6 or more weeks have elapsed since the previous dose.

A 10 mL maintenance dose containing 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase. This dose is given every 3 weeks.

For early breast cancer, pertuzumab, trastuzumab, and hyaluronidase-zzxf’s prescribing information recommends 3 to 6 preoperative cycles and 1 year of postoperative treatment for up to 18 cycles. During treatment, patients with metastatic breast cancer receive pertuzumab, trastuzumab, and hyaluronidase-zzxf until disease progression or unmanageable toxicity.

Health care professionals administer pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneously in the thigh and observe the patient for at least 15 minutes, or 30 minutes following the loading dose. Emergency medications must be readily available for treatment of hypersensitivity or other administration reactions as well.

When preparing pertuzumab, trastuzumab, and hyaluronidase-zzxf for administration:

Visually inspect for particulate matter and discoloration (solution should be clear to opalescent and colorless to slightly brown)

Draw into syringe using transfer needle, and replace needle with syringe closing cap unless using immediately

Store at room temperature for up to 4 hours, or under refrigeration for up to 24 hours

Just prior to administration, attach a 25G to 27G hypodermic injection needle and adjust the volume to 15 mL or 10 mL

Like IV pertuzumab plus trastuzumab, the pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy carries risks of cardiomyopathy, embryo-fetal toxicity, and pulmonary toxicity; its prescribing information includes boxed warnings for these adverse effects (AEs).

Pertuzumab, trastuzumab, and hyaluronidase-zzxf can cause cardiac symptoms including hypertension, arrhythmias, and clinical cardiac failure. In the FeDeriCa study’s pertuzumab, trastuzumab, and hyaluronidase-zzxf arm, 1.2% and 0.8% of patients experienced New York Heart Association (NYHA) Class II and NYHA Class III/IV cardiac failure, respectively.

Before starting pertuzumab, trastuzumab, and hyaluronidase-zzxf, patients should undergo a thorough cardiac assessment with evaluation of left ventricular ejection fraction (LVEF). Providers should assess LVEF every 12 weeks throughout treatment, and the prescribing information provides criteria for when to hold, restart, or permanently discontinue pertuzumab, trastuzumab, and hyaluronidase-zzxf based on LVEF changes. After completing pertuzumab, trastuzumab, and hyaluronidase-zzxf, patients should have their LVEF assessed every 6 months for at least 2 years.

The embryo-fetal toxicity warning is based on IV trastuzumab post-marketing reports and IV pertuzumab animal studies. These identified a risk of oligohydramnios, or low amniotic fluid volume, potentially leading to pulmonary hypoplasia, skeletal abnormalities, delayed fetal kidney development, and embryo-fetal or neonatal death. Pertuzumab, trastuzumab, and hyaluronidase-zzxf’s prescribing information advises females of reproductive potential to use effective contraception during, and for 7 months after, treatment.

IV trastuzumab can cause serious pulmonary toxicity, and pertuzumab, trastuzumab, and hyaluronidase-zzxf is expected to carry the same risk. Pulmonary AEs may include dyspnea, interstitial pneumonitis, acute respiratory distress syndrome, pleural effusions, and pulmonary infiltrates, edema, or fibrosis. Patients with preexisting lung disease or tumor involvement may be at higher risk.

In the FeDeriCa study, 1.2% of pertuzumab, trastuzumab, and hyaluronidase-zzxf-treated patients experienced hypersensitivity reactions, and 21% experienced other administration-related reactions. Health care providers administering pertuzumab, trastuzumab, and hyaluronidase-zzxf should monitor patients for angioedema, breathing problems, chest pain, dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, or injection site pain.

Based on data from IV trastuzumab clinical trials, pertuzumab, trastuzumab, and hyaluronidase-zzxf is expected to increase chemotherapy-induced neutropenia risk.

 is a pharmacist at Johnson Memorial Hospital in Stafford Springs, Connecticut.

Tan A, Im S, Mattar A, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomized, open-label, multicentre, non-inferiority, phase 3 study.

https://doi.org/10.1016/S1470-2045(20)30536-2

FDA approves breast cancer treatment that can be administered at home by health care professional [News release]. FDA. June 29, 2020. Accessed July 27, 2021. 

https://www.fda.gov/news-events/press-announcements/fda-approves-breast-cancer-treatment-can-be-administered-home-health-care-professional

Phesgo. Prescribing information. Genentech; 2020. Accessed July 27, 2021. 

https://www.gene.com/download/pdf/phesgo_prescribing.pdf

Approved by the FDA on June 29, 2020, the pertuzumab, trastuzumab, and hyaluronidase-zzxf combination therapy with chemotherapy offers several advantages to the standard treatment of pertuzumab plus trastuzumab with chemotherapy for breast cancers with HER2 overexpression.