Long-Term Findings Solidify Role of HER2-Targeted Therapy in Early HER2+ Breast Cancer

Francisco J. Esteva, MD, PhD

Data surrounding perioperative treatment approaches for patients with early-stage HER2-positive breast cancer have helped establish standards of care in this setting, and ongoing clinical trials are looking at ways to de-escalate or escalate therapy in the neoadjuvant and adjuvant settings based on individual patient and disease characteristics, according to Francisco J. Esteva, MD, PhD.

“HER2[-targeted] therapy in patients with stage II/III [HER2-positive] breast cancer is the standard of care. We can deliver the [HER2] antibodies trastuzumab [Herceptin] and pertuzumab [Perjeta] either intravenously [IV] or subcutaneously, and they're both equally effective,” Esteva explained in an interview with OncLive^®.

In the interview following an OncLive State of the Science Summit™ (SOSS) on breast cancer, which he chaired, Esteva highlighted data from several key trials across the early-stage HER2-positive breast cancer landscape and their clinical impact. He also discussed the importance of evaluating the de-escalation of therapy in this population.

Esteva is the interim chief of the Division of Hematology and Oncology and the chief of Breast Medical Oncology at Lenox Hill Hospital, and he serves as the director of Breast Medical Oncology for Northwell Health, in New York, New York.

OncLive: What is the current treatment landscape for early HER2-positive breast cancer?

Esteva: The landscape of early-stage HER2-positive breast cancer has evolved over the last few years. Nowadays, unless a patient has a small tumor with negative lymph nodes, we generally prefer to use neoadjuvant HER2-targeted therapy. When [patients] achieve a pathologic complete response [pCR] to neoadjuvant therapy in HER2-positive early breast cancer, those patients have the best outcomes in terms of event-free survival and overall survival [OS].

Pivotal studies [evaluated neoadjuvant] trastuzumab and pertuzumab plus a taxane with or without carboplatin. The phase 2 NeoSphere trial [NCT00545688] evaluated docetaxel, trastuzumab, and pertuzumab, and the phase 2 TRYPHAENA trial [NCT00976989] added carboplatin to docetaxel, trastuzumab, and pertuzumab. [At the SOSS], I discussed the different backbones of chemotherapy that are generally used, including docetaxel or weekly paclitaxel, [which] can also be used in this setting with similar results.

We also discussed how to deliver the [anti-HER2] antibodies, whether it's IV or subcutaneous. We also [explored] the role of ado-trastuzumab emtansine [T-DM1; Kadcyla] in patients who have residual disease after neoadjuvant therapy.

[With the current treatment options], the results are quite good [in early-stage HER2-positive breast cancer], and the pCRs are high in general. For patients at lower risk [of recurrence], there are clinical trials trying to de-escalate the amount of chemotherapy given to these patients. For example, this could meaning giving the [anti-HER2] antibodies by themselves without chemotherapy with close monitoring, or in combination with hormone therapy in the estrogen receptor [ER]–positive [population]; these are the types of clinical trials that we're trying to do to de-escalate the chemotherapy that we give prior to surgery.

After surgery, if a patient achieves a pCR, we generally continue the antibody therapy by itself; however, in patients with residual disease, we may have to escalate the treatment, which does not mean only considering T-DM1. We are also doing clinical trials and adding new drugs, like tucatinib [Tukysa] fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd].

What was the clinical impact of the NeoSphere trial?

NeoSphere was the pivotal FDA registration trial for pertuzumab. This was the first time that any medication, any drug, was approved in the neoadjuvant setting using pCR as the primary end point. Prior to that, the FDA always required [an improvement in] disease-free survival [DFS] or OS for approval. In this study, [417] patients were [randomly assigned] to 4 different groups: docetaxel and trastuzumab for 4 cycles prior to surgery; docetaxel, trastuzumab, and pertuzumab for 4 cycles prior to surgery; trastuzumab and pertuzumab without chemotherapy; and docetaxel and pertuzumab.

The pCR [rate] was higher in the group treated with docetaxel, trastuzumab, and pertuzumab. Post-operatively, patients received chemotherapy with an anthracycline, so the long-term effects may also be influenced by that; however, the pCR rate at the time of surgery was based only on those 4 cycles of docetaxel, trastuzumab, and pertuzumab.

How did the TRYPHAENAtrial help inform clinical practice?

TRYPHAENA was a supportive study, and the primary end point was to look at cardiac safety in patients receiving anthracycline, trastuzumab, and pertuzumab. Two of the arms included FEC [fluorouracil, epirubicin, and cyclophosphamide] in sequence with the triplet combination, and the third arm was docetaxel, carboplatin, trastuzumab, and pertuzumab for 6 cycles. They also collected the pCR rate, which was also high in this population.

What was the clinical impact of results from the phase 3 FeDeriCa trial (NCT03493854)?

The FeDeriCa trial [randomly assigned] patients to the standard of care at the time of IV trastuzumab and pertuzumab given [plus chemotherapy] compared with a subcutaneous formulation of trastuzumab plus pertuzumab [Phesgo]. This was a neoadjuvant trial, so these treatments were given prior to definitive surgery.

The pharmacokinetics in both groups were basically the same, and the pCR rate, which was a secondary end point, was also similar for IV vs subcutaneous therapy. [Data from this study] led to the [FDA] approval of [trastuzumab and pertuzumab] as a subcutaneous formulation, which can be used in the neoadjuvant setting.

Moving on to the phase 2 PHranceSCa trial (NCT03674112), what were the key findings and their impact?

PHranceSCa randomly assigned patients initially to receive subcutaneous vs IV trastuzumab and pertuzumab. Patients then crossed over to the other approach, and they were asked to choose which one they preferred after being exposed to both. The majority of patients chose the subcutaneous formulation. There was also an update [from the trial presented] at the 2023 ESMO Congress showing that long-term effects were very similar between both approaches.

What did data from the phase 3 KATHERINE trial (NCT01772472) evaluating T-DM1 for patients with HER2-positive residual breast cancer?

The KATHERINE study was conducted in patients with residual disease following neoadjuvant HER2-targeted therapy. Patients were [randomly assigned] to T-DM1 or continuation of trastuzumab, and patients who received T-DM1 had a higher DFS and OS.

An update at the 2023 San Antonio Breast Cancer Symposium showed an improvement in 7-year invasive DFS for patients receiving T-DM1 compared with trastuzumab in the adjuvant setting, and the OS was improved in patients receiving T-DM1 compared with trastuzumab. Long-term cardiac effects were rare in both groups.

T-DM1, as of today, is the standard of care for patients with residual, invasive disease after neoadjuvant HER2-targeted therapy.

How have the trials and data regarding perioperative treatment approaches in HER2-positive breast cancer helped shape the treatment paradigm?

The choice of taxane, even though most clinical trials were done with docetaxel, is [not critical], [as] evidenced by studies producing similar results [between each backbone]. The way monoclonal antibodies are delivered is not as important in terms of efficacy. There are patient preferences and time savings if you use the subcutaneous formulation, but that's a personal choice by the physicians and the patients. It is something that we have available. It's also important to consider clinical trials to de-escalate or escalate therapy, depending on the situation, to move the field forward.