New Subcutaneous, Oral, and Intravenous Therapies Transform Treatment in Early-Stage HER2+ Breast Cancer

Francisco Javier Esteva, MD, PhD

The incorporation of subcutaneous trastuzumab (Herceptin), pertuzumab (Perjeta) and hyaluronidase-zzxf (Phesgo) as neoadjuvant or adjuvant treatment of patients with early-stage HER2-positive breast cancer has solidified a new standard of care in the paradigm, said Francisco Javier Esteva, MD, PhD, who added that additional agents, such as neratinib (Nerlynx) and ado-trastuzumab emtansine (T-DM1; Kadcyla) have further improved outcomes for this patient population.

“Patients with early-stage HER2-positive breast cancer have an excellent prognosis. They used to have the worst prognosis, but because of therapies, including trastuzumab, pertuzumab, T-DM1, and neratinib, these patients have the best prognosis,” said Esteva.

“We have to know how to use these therapies in the right sequence and combination. The incorporation of neoadjuvant therapy is extremely important for patients with high-risk early-stage breast cancer so we can identify patients who do not achieve pathologic complete responses [pCRs]. Then, we can use additional therapies, as well as hopefully new therapies, to try to improve their outcomes even more.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on breast cancer, Esteva, chief of Breast Medical Oncology at Northwell Health Cancer Institute, discussed the current approach to treating patients with early-stage HER2-positive breast cancer, unmet needs in the space, and future directions with neratinib and T-DM1.

OncLive®: What does sequencing currently look like for patients with early-stage HER2-positive breast cancer?

Esteva: In early-stage HER2-positive breast cancer, we have seen tremendous advances in the treatment [of patients]. In the adjuvant setting, most patients with small tumors receive treatment with trastuzumab and paclitaxel based on the APT trial [NCT00542451]. That is what I would consider the standard of care.

In patients with high-risk HER2-positive breast cancer, meaning patients whose tumors are more than 2 cm or those who have involvement of axillary lymph nodes, we prefer to treat with neoadjuvant chemotherapy, trastuzumab, and pertuzumab based on the pivotal NeoSphere study [NCT00545688] and others that showed that the addition of pertuzumab to trastuzumab and taxane-based chemotherapy improved pCR and disease-free survival [DFS]. This [regimen] has become the standard of care. The chemotherapy backbone for those patients could be paclitaxel or docetaxel with or without carboplatin. There is also a sequential approach where we use a taxane, trastuzumab, and pertuzumab [THP] followed by an anthracycline-based therapy.

We all have different preferences, and we can choose from several options based on patient characteristics.

When patients receive neoadjuvant HER2-targeted therapy and chemotherapy, if they do not achieve a pCR, they will be treated with T-DM1 based on the KATHERINE study [NCT01772472]. [In that trial], patients with residual disease in the breast or lymph nodes were randomized to T-DM1 or trastuzumab alone. Now, we would use adjuvant trastuzumab and pertuzumab [as a comparator arm]. The [results of] that study showed a significant improvement in [invasive] DFS and overall survival in patients who received T-DM1 [vs trastuzumab alone]. That [agent has] become standard of care [in that setting].

Recently, we saw a publication from the FeDeriCa trial [NCT03493854] where a new formulation of trastuzumab and pertuzumab was compared with the standard intravenous [IV] trastuzumab and pertuzumab approach. The data showed similar pharmacokinetics, safety, and efficacy for a fixed-dose subcutaneous combination of trastuzumab and pertuzumab vs the IV therapy. This is an important combination that has been FDA approved. [The subcutaneous formulation] is something we are beginning to use in our clinic because it saves patients’ time and usage of resources. It’s also been shown to be quite favorable in terms of pharmacokinetics, safety, and efficacy.

What improvements still need to be made regarding the treatment of this patient population?

The unmet needs in patients with early-stage HER2-positive breast cancer are improvements for patients who do not achieve a pCR to neoadjuvant trastuzumab, pertuzumab, and chemotherapy. The standard of care now for those patients is T-DM1, which is an improvement over a continuation of trastuzumab with or without pertuzumab. We need to improve on that since some patients still develop metastatic disease after trastuzumab, pertuzumab, chemotherapy, and T-DM1. Developing new therapies for patients who develop metastasis will be important.

What trials are poised to further change this landscape?

The APHINITY trial [NCT01358877] showed an improvement in DFS with [the addition of] pertuzumab to trastuzumab and chemotherapy. For patients who complete adjuvant therapy with trastuzumab, pertuzumab, and chemotherapy, followed by T-DM1, [the ExteNET study (NCT00878709)] looked at neratinib as extended adjuvant therapy. That study showed an improvement [in outcomes], especially in tumors that were estrogen receptor [ER] positive. [Neratinib represents] another option that is an important addition to the early-stage breast cancer [armamentarium] that improves DFS after standard therapy.

Also, there are studies looking at hormonal therapy; however, in HER2-positive breast cancer, HER2-targeted therapies really take preference. All patients who have ER-positive cancer will, of course, proceed with adjuvant endocrine therapy. New therapies are also being tested, such as [fam-]trastuzumab deruxtecan[-nxki; Enhertu] and tucatinib [Tukysa]. These have been [useful agents] in the metastatic setting, so they are being incorporated into early-stage clinical trials.