By: Lyana Sayilar, PharmD Candidate c/o 2020

Approved on April 17, 2020, tucatinib (Tukysa^TM) is indicated to aid in the treatment of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer and could be a potential add-on therapy.³ Among the different types of breast cancers, an increase of HER2, a transmembrane glycoprotein consisting of intracellular and extracellular domains, on the surface of breast cancer cells leads to proliferation and may metastasize to other parts of the body. Therefore, HER2-targeted therapy is useful for this type of breast cancer.⁸

The first-line therapy of HER2+ metastatic breast cancer is pertuzumab + docetaxel + trastuzumab. Although there is no experimental causation of docetaxel altering the permeability of the blood brain barrier to increase the entry of tumor cells into the brain, there is an association that brain metastases increase while on taxane treatment.⁴ In many other countries, paclitaxel is used instead of docetaxel because it further increased progression-free survival and reduced the occurrence of neutropenia.¹⁰ The second-line agent for HER2+ metastatic breast cancer, ado-trastuzumab emtansine (Kadcyla®), consists of a humanized monoclonal antibody covalently bound to a cytotoxin. Third-line treatment is a combination of lapatinib, a tyrosine kinase inhibitor, and an antimetabolite, capecitabine.^5,6,8

Furthermore, tucatinib is a highly selective tyrosine kinase inhibitor of the intracellular domain of HER2, a tyrosine kinase protein, preventing phosphorylation of HER2 receptors on tumor cells and proliferation of tumor cells. It is indicated for use in neurologically stable patients with brain metastases who are not in need of urgent surgery or radiation and in patients without brain metastases, either of whom have tried treatment with at least one medication against the proliferation of HER2 receptor. Tucatinib is taken along with the anti-HER2 antibody, trastuzumab, and capecitabine.¹

A randomized (2:1), double-blind, placebo-controlled trial, HER2CLIMB, was conducted at 157 sites worldwide with the majority of the patients white females and less than 75 years old.² The primary endpoint of the trial was duration of progression-free survival. The first 480 patients were randomized to receive tucatinib + trastuzumab + capecitabine or placebo + trastuzumab + capecitabine. There was a median 2-month difference in progression-free survival, favoring the tucatinib combination.¹ In one year, the progression-free survival of the tucatinib combination was 33.1 percent as compared to 12.3 percent with placebo combination (95% CI [0.42-0.71]; p-value <0.001).²

Additionally, secondary endpoints, such as overall survival and progression-free survival in patients with brain metastases, were measured in 612 patients. At 2 years, 44.9 percent in the tucatinib combination survived as compared to 26.6 percent in the placebo combination group (95% CI [0.50-0.88]; p= 0.005).The median survival at 2 years was 21.9 months for the tucatinib combination and 17.4 months for the placebo combination. Progression-free survival in 1 year in patients with brain metastases was 24.9 percent for the tucatinib combination and 0 percent for the placebo combination (95% CI [0.34-0.69]; p-value <0.001). There was a median 2-month difference in progression-free survival, favoring the tucatinib combination.² The data seems promising for patients with brain metastases. Since tucatinib and lapatinib are in the same drug class, comparing tucatinib + trastuzumab + capecitabine and lapatinib + trastuzumab + capecitabine in brain metastatic patients may be beneficial, although there is no head-to-head trial comparing the two combinations. In a study in China, patients who took lapatinib + trastuzumab + capecitabine as first-line for brain metastases had a statistically significant median progression-free survival of 20.7 months than if taken as second-line therapy (12.3 months) or third-line therapy (7.3 months).⁹ Therefore, the lapatinib combination seems more effective when taken earlier, which may foreshadow the benefit of tucatinib in brain metastatic patients. 

Tucatinib resulted in fetal deformities in animal studies and should be avoided in pregnant women. Women of reproductive age should be reminded to use contraception during treatment with tucatinib + trastuzumab + capecitabine and for one week after the last dose. The combination should be avoided during breastfeeding as it may appear in breast milk. Another warning to note is it may cause sterility in men and women.¹

Additionally, drug-drug and drug-food interactions must be considered. Concomitant use of tucatinib with strong CYP3A4 inducers, moderate CYP28C inducers, strong CYP2C8 inhibitors, or with P-gp substrates result in dose adjustments. Renal and hepatic function should be assessed prior to initiating tucatinib + trastuzumab + capecitabine. The combination is not recommended if the CrCl is less than 30 mL/min. For patients with Child-Pugh C hepatic impairment, the dose should be reduced from 300 mg tucatinib orally twice daily to 200 mg twice daily.¹

Tucatinib can be considered as a treatment option for HER2+ metastatic breast cancer with and without brain metastases. Up to 50 percent of patients with HER2+ metastatic breast cancer suffer from brain metastases and half of those patients unfortunately lose their lives, but there is hope for improvements as research continues.⁷     

Sources:

1. TUKYSA^TM (tucatinib) [package insert]. Bothell, WA; Seattle Genetics, Inc.; Revised 04/17/2020.
2. Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382(7):597-609. doi: 10.1056/NEJMoa1914609
3. Goodman A. Emerging Alternatives in the Third-Line Setting for Metastatic HER2-Positive Breast Cancer. The ASCO Post. https://www.ascopost.com/issues/december-10-2019/emerging-alternatives-in-the-third-line-setting-for-metastatic-her2-positive-breast-cancer/. Published 12/10/2019.
4. Bernatz S, Ilina EI, Devraj K, et al. Impact of Docetaxel on blood-brain barrier function and formation of breast cancer brain metastases. J Exp Clin Cancer Res. 2019;38(1):434. doi: 10.1186/s13046-019-1427-1.
5. Shah N, Mohammad AS, Saralkar P, et al. Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol Res. 2018;132:47-68. doi: 10.1016/j.phrs.2018.03.021
6. KADCYLA® (ado-trastuzumab emtansine) [package insert]. South San Francisco, CA; Genentech, Inc.; Revised 05/20/2019.
7. Duchnowska R, Loibl S, Jassem J. Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer. Cancer Treat rev. 2018;67:71-77. doi: 10.1016/j.ctrv.2018.05.004
8. Schott A. Systemic treatment for HER2-positive metastatic breast cancer. UpToDate. https://www-uptodate-com.jerome.stjohns.edu/contents/systemic-treatment-for-her2-positive-metastatic-breast-cancer?search=her2%20positive%20metastatic%20breast%20cancer&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Published 01/28/2020. Last Updated 05/06/2020.
9. Li Y, Gong C, Lu Q, et al. Real-World Data of Triplet Combination of Trastuzumab, Lapatinib, and Chemotherapy in HER2-Positive Metastatic Breast Cancer: A Multicenter Retrospective Study. Front Oncol. 2020;10:271. doi: 10.3389/fonc.2020.00271
10. Bachelot T, Ciruelos E, Schneeweiss A, et al. Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). ScienceDirect. https://www-sciencedirect-com.jerome.stjohns.edu/science/article/pii/S0923753419311615?via%3Dihub#!. Published 01/06/2020.  

Published by Rho Chi Post