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Hurvitz Highlights Emerging Agents for Heavily Pretreated HER2+ Breast Cancer

Brandon Scalea
Published: Thursday, Mar 21, 2019

Sara A. Hurvitz, MD
Sara A. Hurvitz, MD
While there are well-established standard therapies for first- and second-line settings in patients with HER2-positive metastatic breast cancer, Sara A. Hurvitz, MD, said that a number of novel agents and combinations are poised to shape later lines of treatment.

“The number of therapies in development right now is quite phenomenal, but it is a brave company to take these emerging therapies on head-to-head in the frontline setting or second-line setting and challenge the current standards,” said Hurvitz, director of the Breast Oncology Program and medical director of the Clinical Research Unit at the University of California, Los Angeles Jonsson Comprehensive Cancer Center.

For example, the selective oral TKI tucatinib is being combined with trastuzumab (Herceptin) and capecitabine in the hopes of tackling the challenge of central nervous system (CNS) metastases. In an open-label, nonrandomized phase Ib study, 61% of patients with measurable disease treated with this 3-drug combination had an objective response. In an exploratory analysis, a brain-specific response was observed in 5 of 12 patients (42%) with CNS metastases who were treated with the recommended phase II dose of 300 mg twice daily of tucatinib.

Other agents, such as margetuximab, trastuzumab deruxtecan (DS-8201), neratinib (Nerlynx), and checkpoint inhibitors have also shown promise in early studies and are being evaluated in larger phase II/III trials.

In an interview with OncLive, Hurvitz discussed recent updates in the paradigm and promising therapeutic strategies on the horizon for patients with HER2-positive metastatic breast cancer.

OncLive: What is the current treatment landscape for patients with HER2-positive metastatic breast cancer?

Hurvitz: It's a really exciting time to be treating patients with HER2-positive metastatic breast cancer because of the many therapeutic options we now have available. The standard of care is to treat patients in the frontline setting with trastuzumab, pertuzumab (Perjeta), and a taxane. The taxane is given for 4 to 6 cycles, and then the patients go on to maintenance trastuzumab and pertuzumab. That is the gold standard based on findings from the CLEOPATRA study, which showed a significant improvement in overall survival (OS) with that triplet strategy. The second gold standard is second-line ado-trastuzumab emtansine (T-DM1; Kadcyla), which is an antibody-drug conjugate (ADC) that targets HER2. This is the gold standard based on data from the EMILIA study.

Therefore, there aren't a whole lot of questions about what you should treat your newly diagnosed patients with or what you should use as second-line therapy. After that, we have multiple different therapeutic options we can utilize, including lapatinib-based therapy, trastuzumab plus chemotherapy, or trastuzumab plus lapatinib. While we have several treatment options available including lapatinib, trastuzumab, pertuzumab, and T-DM1, there are myriad therapies in clinical trials right now.

What are some of these agents that are on the horizon?

There are a number of agents that are really exciting right now. One of them is neratinib, which is already FDA approved in the adjuvant setting, after completion of 1 year of adjuvant trastuzumab. Neratinib is being combined with capecitabine and being compared with lapatinib (Tykerb) plus capecitabine in the phase III NALA study. There was a press release indicating that NALA met its primary endpoint; neratinib plus capecitabine did demonstrate superior progression-free survival (PFS). Those results are going to be presented at an upcoming meeting, and we are all eagerly anticipating them.

Another drug that has been given a lot of press and excitement recently is another oral TKI called tucatinib. This is a selective HER2 inhibitor, and because it is selective, it may [be associated with] less gastrointestinal (GI) toxicity. In phase I studies, tucatinib showed very good response rates combined with trastuzumab, capecitabine, or both.

The ongoing phase II randomized HER2CLIMB trial is comparing tucatinib plus trastuzumab/capecitabine to placebo plus trastuzumab/capecitabine. The interesting aspect of this study is that they are allowing patients to enroll who have actively progressing CNS metastases. Most studies exclude these patients. This drug does penetrate the blood-brain barrier, and objective responses in the CNS have been noted in the phase I study. That is particularly exciting for our patients given that one-third to one-half of patients with HER2-positive metastatic breast cancer will develop brain metastases during the course of their disease.

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