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CNS Metastases Remain Unmet Need in HER2+ Breast Cancer

Angelica Welch
Published: Tuesday, Aug 14, 2018

Kevin Kalinsky, MD

Kevin Kalinsky, MD

The rate of central nervous system (CNS) involvement is the most significant unmet need in the management of patients with HER2-positive metastatic breast cancer, according to Kevin Kalinsky, MD.

Investigators hope to address this ongoing challenge with a few targeted agents, including neratinib (Nerlynx), which is currently FDA approved for the treatment of patients with early-stage, HER2-positive breast cancer following postoperative trastuzumab (Herceptin).

The phase II TBCRC 022 trial evaluated the combination of neratinib plus capecitabine for patients with HER2-positive breast cancer with brain metastases. Results demonstrated that neratinib plus capecitabine has activity in this patient population, with a reduction in volumetric sum of target CNS lesions observed in 18 patients (49%). The median time to CNS progression was 5.5 months, and the progression-free survival rate at 6 months was 38%.

Additional agents coming down the pike may address the CNS metastases challenge, Kalinsky said, including tucatinib (ONT-380). The phase II HER2CLIMB trial randomizing patients with HER2-positive breast cancer with or without CNS metastases to tucatinib plus capecitabine and trastuzumab versus placebo plus capecitabine and trastuzumab is currently ongoing (NCT02614794). Progression-free survival is the primary endpoint of this study, with secondary endpoints being overall survival (OS) and quality of life.

In an interview with OncLive during the 17th Annual International Congress on the Future of Breast Cancer® East, Kalinsky, assistant professor of Medicine, Division of Hematology and Oncology, NewYork-Presbyterian Hospital/Columbia University Medical School, discussed the current treatment landscape of metastatic HER2-positive breast cancer, the potential for immunotherapy, and what is on the horizon for patients in this population who develop brain metastases.

OncLive: Please Provide an overview of your lecture on metastatic HER2-positive breast cancer.

Kalinsky: We spoke about HER2-positive metastatic breast cancer and the significant advances that have been made in this disease. We reviewed the drugs that had been approved, including the monoclonal antibodies like pertuzumab (Perjeta) and ado-trastuzumab emtansine (T-DM1; Kadcyla). Then, we focused on some new therapies coming down the pike that are pretty exciting.

We broke out the talk into different classes of drugs. This included neratinib, which is not yet approved in metastatic HER2-positive breast cancer, but there is some early brain penetration data with it. We also discussed tucatinib, which is a next-generation selective HER2 tyrosine kinase inhibitor that is currently in a randomized phase II trial. Then, we spoke about some exciting monoclonal antibodies that were reported about at the 2018 ASCO Annual Meeting, which showed very significant responses. For instance, there is DS-8201a, which has fast track designation from the FDA. Then, we concluded with the role of immunotherapy, and some early data presented at the 2017 San Antonio Breast Cancer Symposium.

How has treatment for HER2-positive metastatic breast cancer evolved over the last 2 years?

It has significantly changed based upon the results of the CLEOPATRA study, which showed a nearly 15-month OS advantage giving pertuzumab upfront with trastuzumab with docetaxel. We also spoke about the EMILIA study which compared T-DM1 versus capecitabine plus lapatinib (Tykerb) in the second-line setting. There was an OS advantage in that study also. These data have changed the landscape of how we initially treat patients with HER2-positive disease.

One of the things that we are seeing is that around 50% of patients with metastatic disease can develop brain metastases. There has been a focus on identifying drugs that we know have really good CNS penetration, so that we can treat not only the body, but the CNS. There is some good activity for those patients with metastatic disease who have CNS involvement.

You touched on neratinib and tucatinib in patients with brain metastases. What work is going on there?

We spent some time talking about a trial published in the Journal of Clinical Oncology that showed responses in patients who received single-agent neratinib. There was also a study in frontline disease, which is a randomized study that has been published in JAMA Oncology that looked at paclitaxel plus trastuzumab versus paclitaxel plus neratinib. The interesting thing about that study is that the rate of developing CNS progression was [reduced in] half in the neratinib arm. We are awaiting the results of the NALA study, which is a randomized phase III registration trial that is comparing capecitabine plus neratinib versus capecitabine plus lapatinib.

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