In 2020 alone, there will be roughly 276,480 newly diagnosed cases of invasive breast cancer and 48,530 cases of non-invasive breast cancer.¹ It is expected that 42,170 women will pass away from breast cancer in one year. While breast cancer also affects men, these numbers only include women.¹ There are many subsets of breast cancer; however, the subset that is the most difficult to treat is associated with an increased recurrence and has an overall poorer prognosis. This subset is found in patients expressing human epidermal growth factor receptor 2 (HER2) in cancer cells.² Although there have been breakthroughs in the treatment of HER2- positive (HER2+) breast cancers, there is still a need to develop therapies for HER2+ metastatic and unresectable breast cancers.

           
The current initial standard of therapy for HER2+ breast cancer is a 21-day cycle regimen involving a combination of trastuzumab (Herceptin®), pertuzumab (Perjeta®), and a taxane such as docetaxel (Taxotere®) or paclitaxel (Abraxane®). The combination of pertuzumab with trastuzumab is used only in treatment-naïve patients. The primary agent that requires close monitoring for safety and efficacy is the taxane. It has a high incidence rate of adverse effects which include, but are not limited to, fever, electrocardiogram abnormalities (specifically associated with left ventricular ejection fraction [LVEF]), and myalgia. Comparatively, trastuzumab and pertuzumab require relatively little monitoring except an echocardiogram for trastuzumab-induced cardiotoxicity.^3,4 Efficacy monitoring parameters include assessing for clinical failure (clinical worsening as marked by new onset of significant symptoms of toxicity or declining patient performance based on the Eastern Cooperative Oncology Group [ECOG] scoring system) formation of new metastases, or growing size of known metastases. Furthermore, if a patient suffers from clinical treatment failure, then the chosen regimen should be reevaluated which includes an assessment of the drug combination and current cancer staging prior to selecting the next course of therapy. In the past year, two drugs have received Food and Drug Administration (FDA) approval for resistant forms of HER2+ breast cancer: tucatinib (Tukysa®) and fam-trastuzumab deruxtecan-nxki (Enhertu®). As multiple options are now available for treatment resistant HER2+ breast cancer, a review regarding use of each in patients and their place in therapy for breast cancer treatment is warranted.

First, fam-trastuzumab deruxtecan-nxki was approved in December 2019 for patients with unresectable or metastatic HER2+ breast cancer who have failed two or more HER2+ targeted therapies.⁵ Fam-trastuzumab deruxtecan-nxki is a humanized monoclonal antibody that binds HER2 receptors on tumor cells, causing DNA damage resulting in apoptosis. By targeting cells only with HER2 markers, the medication does not significantly affect healthy cells which resulted in the absence of cardiotoxicity as a side effect. Typical dosing for fam-trastuzumab deruxtecan-nxki is 5.4 mg/kg infused once every three weeks with no specific recommendations for renal or hepatic impairment. Monitoring parameters include complete blood count (CBC), LVEF, pregnancy status (category X), signs and symptoms of pneumonitis, and infusion reactions (prior to treatment initiation and with each dose).

In addition, the FDA approval for fam-trastuzumab deruxtecan-nxki was strongly based on the positive results from the ENHERTU study.⁶ The study enrolled 184 female patients with unresectable or metastatic breast cancer refractory to two or more targeted HER2 therapies. Overall, 60.4% of patients had a response to treatment, of which 4.3% had a complete response and 56% achieved a partial response. However, there was a lack of diversity of specific patient population during this trial.

Tucatinib was approved in April 2020 for the treatment of advanced unresectable or metastatic HER2+ breast cancer patients that have previously failed at least one other treatment.7 Mechanistically, tucatinib prevents tumor cell signaling and proliferation resulting in anti-tumor activity by inhibiting phosphorylation of both HER2 and HER3. When combined with trastuzumab, synergistic anti-tumor activity is achieved. The standard dosing for tucatinib is 300 mg by mouth taken twice daily, usually in conjunction with trastuzumab and capecitabine. It can be taken with or without food but should not be given with moderate or strong CYP2C8 inducers or strong CYP3A4 inducers. Tucatinib is not recommended for patients with renal impairment with creatinine clearance less than 30 mL/min or Child-Pugh Class C. It can be used in Child-Pugh Class A or B at a decreased dose of 200 mg. During treatment, additional monitoring may be clinically indicated, including pregnancy status and medication adherence.8 Missed doses should be counted and skipped, and the next dose should be taken at the regularly scheduled time.
 
Tucatinib showed favorable results in the HER2CLIMB study, investigating survival outcomes compared against placebo, which ultimately contributed to its FDA approval.9 Patients in the tucatinib arm of the study had a 46% reduction in disease progression or death, 4.5-month improvement in median overall survival, and doubled antitumor activity when compared to the control arm.

Fam-trastuzumab derxtecan-nxki and tucatinib both show promising results based on landmark trials for patients who have failed standard therapy for HER2+ breast cancer with metastatic or unresectable status. Both drugs should only be recommended as last line therapy due to lack of scientific data, including long-term follow-up data and significant adverse effects.  As more clinical data is researched and published, there is a potential for these drugs to change their place in therapy.

1. U.S. Breast Cancer Statistics. Updated June 25, 2020. Accessed September 8, 2020. https://www.breastcancer.org/symptoms/understand_bc/statistics.
   
2. Systemic Treatment for HER2-positive MBC Metastatic Breast Cancer. Updated August 31, 2020. Accessed September 8, 2020. https://www.uptodate.com/contents/systemic-treatment-for-her2-positive-metastatic-breast-cancer.
   
3. Herceptin [package insert]. South San Francisco, CA: Genentech, Inc. 2010.
   
4. Perjeta [package insert]. South San Francisco, CA: Genentech, Inc. 2012.
   
5. Enhertu [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc. 2019.
   
6. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2019;382:610-621.
   
7. Tukysa [package insert]. Bothell, WA: Seattle Genetics, Inc. 2020.
   
8. Tukysa Important Facts. Published 2020. Accessed September 8, 2020. https://seagendocs.com/TUKYSA_Important_Facts.pdf.
   
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.