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Jeremy Whalen, PharmD, BCOP
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Integrating Trastuzumab Biosimilars and HER2-Directed Therapies into HER2-Positive Breast Cancer Management
Sandra Cuellar, PharmD, BCOP
Managed Care Considerations for Navigating Biosimilar and HER2-Directed Therapies for the Treatment of HER2-Positive Breast Cancer

Integrating Trastuzumab Biosimilars and HER2-Directed Therapies into HER2-Positive Breast Cancer Management

Sandra Cuellar, PharmD, BCOP
The approval of the humanized monoclonal antibody trastuzumab in 1998 changed the trajectory of treatment and subsequent outcomes for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and is now the standard of care in the neoadjuvant, adjuvant, and metastatic settings. However, as with most biologic drugs, trastuzumab comes with a relatively high price tag compared with traditional cytotoxic chemotherapy and contributes to healthcare budgets. Three engineered products related to trastuzumab—2 antibody-drug conjugates, ado-trastuzumab emtansine and fam-trastuzumab deruxtecan-nxki, as well as the subcutaneous trastuzumab/hyaluronidase—have since been approved and have expanded the treatment options for this patient population. The approval of 5 trastuzumab biosimilars as of the end of 2019 holds the promise of considerable cost savings, but challenges to integrating their use into patient care must be addressed. Barriers to their use, including physician uncertainty to switch patients from the reference drug to the therapeutic biosimilar and patients’ lack of understanding about biosimilars, are common in the United States. It is also important that all stakeholders, including managed care professionals, pharmacists, and practice administrators, understand how to incorporate trastuzumab biosimilars into formulary discussions, clinical care plans and processes, and educational initiatives for healthcare providers and patients.

Am J Manag Care. 2020;26:S32-S40.

An estimated 268,600 new cases of invasive breast cancer were diagnosed in women in 2019, making it the most common cancer in women in the United States. Although approximately 42,260 women died from the disease that year, the overall death rate from breast cancer has fallen by 40%, from 33.2 per 100,000 in 1989 to 20.0 per 100,000 in 2016.1 This is due not only to earlier diagnosis through screening but also to the emergence of agents with new mechanisms of action and more targeted therapies that address the presence or absence of 3 key molecular markers in breast cancer: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2). These molecular markers are the basis for classifying breast cancer into 3 subtypes—HER2-positive, hormone receptor-positive (ER+ and/or PR+), or triple-negative—and for determining the appropriate initial treatment approach in early-stage disease.2 Genomic and molecular testing is now standard practice in patients with advanced-stage breast cancer in order to determine the most appropriate targeted therapies based on hormone and HER2 status as well as PIK3CA, BRCA1, BRCA2, and PD-L1 biomarker status.3

An estimated 15% to 20% of women with newly diagnosed breast cancer have tumors that overexpress HER2. These tumors tend to be more aggressive, more likely to invade lymph nodes, and more likely to recur and metastasize than other subtypes. They have also been historically associated with shorter patient survival compared with hormone receptor–positive breast cancer.2,4 However, with the 1998 approval of trastuzumab, a humanized monoclonal antibody (mAb) that targets the extracellular domain of the HER2 protein, the trajectory of HER2-positive breast cancer shifted dramatically. Based on substantially improved outcomes in multiple clinical trials, including significant survival benefits across all stages of the disease, trastuzumab-based regimens are considered the gold standard of treatment for women with HER2-positive breast cancer.2,3


Cochrane Database of Systematic Reviews found that trastuzumab-based regimens in early breast cancer (EBC) improved overall survival (OS) by 33% (hazard ratio [HR], 0.66; 95% CI, 0.57-0.77; P <.00001) and disease-free survival (DFS) by 40% (HR, 0.60; 95% CI, 0.50-0.71; P <.00001),5 and in the metastatic setting improved OS by 18% (HR, 0.82; 95% CI, 0.71-0.94; P = .004) and progression-free survival by almost 40% (HR, 0.61; 95% CI, 0.54-0.70; P <.00001).6

Dosage and Administration

Trastuzumab has a variety of dosing regimens, with the dose, combination of agents, and duration depending on its use in the neoadjuvant, adjuvant, or metastatic setting. Trastuzumab is administered via intravenous (IV) infusion and requires a loading dose followed by a maintenance dose. The National Comprehensive Cancer Network (NCCN) lists 10 potential regimens in the preoperative and adjuvant settings.3

The NCCN guidelines list 4 potential trastuzumab-containing regimens for metastatic treatment in premenopausal women with trastuzumab in combination with an antiestrogen, either as monotherapy or in combination with lapatinib. For postmenopausal women, the preferred regimens are pertuzumab, trastuzumab, and docetaxel (category 1) or pertuzumab, trastuzumab, and paclitaxel. Several other regimens are also recommended.3 The NCCN notes that an FDA-approved biosimilar is an appropriate substitute for trastuzumab in all settings.3


Overall, trastuzumab is well tolerated and does not require any supportive care medications before or after administration. The most common adverse effects (AEs) affecting at least 5% of women in the adjuvant setting are headache, diarrhea, nausea, and chills (most grade 2 in severity), whereas fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash were the most common AEs affecting at least 10% in the metastatic breast cancer (MBC) setting.7,8

Trastuzumab labeling carries a black box warning of the risk of cardiomyopathy. In the pivotal phase 3 clinical trial published by Slamon and colleagues, combining trastuzumab with anthracyclines caused cardiac dysfunction and heart failure in up to 27% of patients with metastatic disease compared with 7% in the anthracycline monotherapy group.9 Since then, large observational studies have also identified higher rates of cardiotoxicity in women receiving trastuzumab compared with anthracycline alone.10,11 This led to a change in clinical trial design to give the 2 drugs sequentially rather than concurrently, which demonstrated a much lower rate of cardiovascular effects.12 Whether the cardiovascular changes are reversible when trastuzumab is discontinued remains a key question.12


Trastuzumab/hyaluronidase-oysk received FDA approval in February 2019. The product uses a patented drug delivery technology to facilitate subcutaneous (SC) administration, with recombinant human hyaluronidase (also called rHuPH20) acting as a temporary spreading factor. It degrades hyaluronan, a large glycosaminoglycan that otherwise limits SC administration of large volumes of fluid.13 Although delivered SC, this product is not self-administered and must be administered by healthcare professionals in an outpatient setting.

Trastuzumab/hyaluronidase-oysk was compared with trastuzumab IV in the open-label, phase 3, noninferiority HannaH (Enhanced Treatment with Neoadjuvant Herceptin) trial. Eligible patients received 8 cycles of chemotherapy with either fixed-dose SC trastuzumab/hyaluronidase-oysk (600 mg) or IV trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in the neoadjuvant setting. Patients received an additional 10 cycles of SC trastuzumab/hyaluronidase-oysk or IV trastuzumab (according to their initial randomization) for 1 year following surgery.14

Rates of grade 3 or higher AEs were similar in the 2 groups, with neutropenia, leukopenia, and febrile neutropenia most common. However, 21% of patients in the SC group versus 12% of patients in the IV group had serious AEs, primarily infections and infestations (8.1% vs 4.4%).15 With 6 years of follow-up in the 591 women in the intention-to-treat population, the event-free survival rate of 65% (HR, 0.98; 95% CI, 0.74-1.29) with an 84% OS (HR, 0.94; 95% CI, 0.61-1.45) were similar between the SC and IV study groups.

The faster administration time provides a much improved experience for patients as demonstrated in the PrefHER and MetaspHer studies. Results of the multicenter, crossover PrefHER trial, which randomized 240 women undergoing neoadjuvant or adjuvant treatment for HER-positive breast cancer to 4 cycles each of IV trastuzumab or SC trastuzumab/hyaluronidase-oysk, found that 91.5% of women preferred the SC formulation primarily because they spent less time in the clinic.16 Similar results were seen in the MetaspHer study, which randomized 113 women to 3 cycles of trastuzumab/hyaluronidase-oysk SC or trastuzumab IV, followed by 3 cycles of the IV formulation.17 Several studies have been conducted outside the United States attesting to the cost-savings potential of an SC delivery approach for healthcare systems; the savings are accrued from less preparation and delivery time as well as direct medical cost savings.18-24 However, with the quickly evolving biosimilars market, the cost-savings potential of an SC delivery approach is not yet known in the United States.

It remains unknown if trastuzumab/hyaluronidase-oysk SC delivery will pose a threat to uptake of the biosimilars, all of which are administered by IV.25 This version of trastuzumab does increase the potential for reducing the cost of trastuzumab IV therapy by adding more market competition. In evaluating costs, stakeholders must consider the complete episode of care; these include differences in drug administration costs and in revenue potential between the 2 different routes in practice settings.

The phase 3 PERSEPHONE trial was designed to investigate the hypothesis, demonstrated in other studies, that 6-month adjuvant trastuzumab treatment is noninferior to 12-month delivery.26 The open-label, noninferiority trial randomized 4089 patients with HER2-positive EBC to either 6-month or 12-month trastuzumab delivered every 3 weeks IV or SC in combination with chemotherapy. Switching from the IV to the SC route was allowed at the prescriber’s discretion. Eighty-two percent of the trastuzumab cycles were given IV and 18% were given SC. The 6-month cohorts met the primary end point of DFS noninferiority to 12 months of treatment, with increased adherence and fewer cardiac and other serious AEs in the 6-month group.26 A cost analysis estimated an average savings of $12,800 for 6 months of trastuzumab versus 12 months, regardless of administration route, for a 100% cost-effective approach with no decrease in quality of life.27 If such a change were adopted as a standard of practice with biosimilars, the cost savings could be even more significant.

Economic Issues Related to Trastuzumab

As with most biologics, the cost of trastuzumab started high and has continued to climb, even as other biologics with similar mechanisms of action entered the market.28 One potential reason for this price increase is that there has not been competition in the marketplace prior to the advent of trastuzumab biosimilar, SC trastuzumab/hyaludronidase-oysk, and antibody–drug conjugate approvals. Trastuzumab has consistently ranked in the top 20 drugs for sales revenue in the United States, with sales of $2.87 billion in 2018.29

Although trastuzumab’s high price does not limit access for patients with the need for lifesaving treatment in the United States due to coverage of the therapy by Medicare Part B as well as Medicaid plans, there are significant financial impacts to organizations—including practices and health systems—and to patients due to out-of-pocket costs. The cost-effectiveness of trastuzumab with or without concurrent or consecutive therapies in the neoadjuvant, adjuvant, and metastatic setting has been extensively studied, but results vary depending on the setting, breast cancer stage, and treatment regimen.30-33 In a survey of 45 US oncologists, one-third cited high out-of-pocket costs for patients as a barrier to prescribing trastuzumab in the early and curative stages, and 10% reported at least 1 instance of delaying or canceling treatment because of reimbursement issues. Reimbursement issues also played a role in 60% of instances in which physicians did not prescribe the drug in the metastatic setting.34 In the same survey, one-third of physicians reported that they would increase the use of HER2-positive antibody therapy if a lower-cost biosimilar version of trastuzumab were available.34

Ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, and Other Antibody–Drug Conjugates

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