Hurvitz Looks Back and Ahead at Advances in Treating HER2-Positive Breast Cancer

Sara A. Hurvitz, MD

From the 1998 FDA approval of trastuzumab (Herceptin) to the novel agents currently under exploration, significant advances have been made in the treatment of HER2-positive breast cancer.

Trastuzumab made history as the first therapy HER2-targeted therapy, following the discovery of the HER2 gene, which encodes a tyrosine kinase receptor that is a potent mediator of cellular growth and proliferation.

The addition of trastuzumab to chemotherapy in patients with previously untreated metastatic breast cancer led to a significantly higher objective response rate, prolonged time to progression (TTP, 7.4 vs 4.6 months; P <.001), and improved overall survival (OS; 25 vs 20 months; P = .01) compared with chemotherapy alone.

Lapatinib, a dual TKI of HER2 and EGFR, gained FDA approval in 2007. The therapy was the first to show that continuing HER2-targeted therapy after progression on a HER2-targeted regimen improves outcomes. Patients who had already progressed on regimens that included trastuzumab, an anthracycline, and a taxane had a better TTP (8.4 vs 4.4 months; P <.001) when they received lapatinib in combination with capecitabine compared with those who received capecitabine alone.

Pertuzumab, approved in 2012, also furthered the treatment of the disease. Two phase II trials evaluated a pertuzumab-plus-trastuzumab—based therapy in the neoadjuvant setting. In the randomized, multicenter phase II NeoSphere trial, pertuzumab and/or trastuzumab with or without docetaxel were administered for four cycles prior to surgery. In this trial, the use of dual HER2-targeted therapy with pertuzumab and trastuzumab combined with docetaxel had a 45.8% progression-free survival (PFS) rate compared with pertuzumab or trastuzumab plus docetaxel (24% and 29%, respectively).

The Antibody-drug conjugate T-DM1 has also made strides in anti-HER2 therapy. In the TH3RESA trial, a heavily pretreated patient population with advanced HER2-positive breast cancer was randomized to receive T-DM1 compared with physician’s choice therapy. The PFS was significantly improved with T-DM1 compared with physician’s choice (median PFS, 6.2 months vs 3.3 months; P <.001).

Several emerging agents have are also being explored in HER2-positive breast cancer. These include neratinib, a potent pan-TKI that irreversibly inhibits HER2; MM-302, a novel antibody-drug conjugate; and ONT-380, a small-molecule selective inhibitor of HER2, also known as ARRY-380.

In a recent interview with The American Journal of Hematology/Oncology (AJHO), Sara A. Hurvitz, MD, director of the Hematology/Oncology Breast Cancer Program and an associate professor in the Department of Medicine at UCLA, discusses the evolving treatment paradigm of HER2-positive breast cancer and what the future might hold.

AJHO: How has the treatment of HER2-positive breast cancer evolved over the years?

Dr Hurvitz: The discovery of the HER2 alteration literally transformed the landscape for women diagnosed with HER2-positive breast cancer. Previously, it was understood that HER2-positive breast cancer was associated with a more aggressive disease biology and a worse disease-related outcome. However, since the advent of HER2-targeted therapy, there has been a shift in the natural history of this disease.

Now, women can expect a much more positive outcome. First, trastuzumab was developed, a clinical antibody that targets the outside of the HER2 receptor. It was FDA approved in 1998 for metastatic HER2-positive breast cancer because it was associated with improved survival and reduced progression when combined with chemotherapy.

In 2006, trastuzumab was FDA approved for early-stage breast cancer in combination with chemotherapy because it showed improved survival and disease-free survival compared to patients who received only chemotherapy in that setting.

In the past decade, however, three more HER2 targeted therapies have been developed and approved. The first was lapatinib, approved in combination with capecitabine, for patients whose disease was resistant to trastuzumab. This therapy demonstrated an improved time to progression compared to use of capecitabine alone.

Then in 2012, pertuzumab was approved in combination with trastuzumab and taxane. Pertuzumab, a monoclonal antibody that also targets HER2, appeared to synergize with trastuzumab and significantly improve the OS and PFS compared to trastuzumab and taxane alone. In 2013, TDM-1 was FDA approved for the treatment of trastuzumab-resistant metastatic breast cancer that is HER2 positive.

What makes TDM-1 different than other therapies approved in this space?

This is the first antibody-drug conjugant FDA approved for breast cancer. It really is a “smart bomb” type of therapy where the antibody is connected to the cytotoxic chemotherapy, and does not release the chemotherapy until the antibody has bound to the HER2 receptor on the malignant cell and has been taken up inside the malignant cell.

How have these advancements shaped today’s treatment paradigm?

Now, first-line therapy for patients newly diagnosed with HER2-positive breast cancer is taxane plus trastuzumab and pertuzumab. The second-line standard approach is TDM-1. We will continue to treat patients with HER2-targeted therapy in the advanced disease setting, alternating the chemotherapy partner. Patients are now expecting a medium OS of 5 years or even greater at the time of their diagnosis, owing to the HER2-targeted therapies that are available.

Changes have also been made in the neoadjuvant setting, which include the use of pertuzumab and trastuzumab with chemotherapy in the early-disease setting. A number of new exciting molecules are also being evaluated that target this disease, making it a very exciting time to be involved in the treatment of women diagnosed with this type of breast cancer.