CNS Metastases Remain Unmet Need in HER2+ Breast Cancer


Kevin Kalinsky, MD, discusses 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.

Kevin Kalinsky, MD

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.

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

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.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.

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

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.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.

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

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.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.

Are there any immunotherapy agents being looked at in the HER2-positive metastatic space?

We also discussed tucatinib, which also has some interesting data. Tucatinib is a TKI that is a little bit more specific for HER2 as opposed to EGFR, for instance. We spoke about a recently reported, small study of giving capecitabine plus trastuzumab plus tucatinib where we saw some significant responses. There is an ongoing phase II trial called HER2CLIMB looking at that triplet versus a doublet, not including tucatinib. That would be an interesting study, because that is another drug that would give us some CNS activity.There has been a lot of interest with immunotherapy, particularly in triple-negative breast cancer (TNBC), which of all our subtypes, has the most unmet need. Part of the interest with immunotherapy is that there can be high rates of tumor-infiltrating lymphocytes (TILs) in TNBC, but the same is true for HER2-positive disease as well.

There was a study presented at the 2017 San Antonio Breast Cancer Symposium, which looked at giving trastuzumab plus a checkpoint inhibitor. In that study, there was a significant difference in OS between those patients who were PD-L1 positive versus PD-L1 negative. This poses a question: Could there be a small cohort of patients who seem to respond to immunotherapy?

What challenges or unmet needs remain in the metastatic HER2-positive setting?

The other thing that was interesting in that study was that in the PD-L1—positive cohort, the higher rates of TILs seemed to be able to dichotomize those who would likely have a response versus not. This is an early study; there are ongoing studies in HER2-positive breast cancer, even though a lot of our focus has been on TNBC.The number 1 thing is the rate of CNS involvement. As I said, about 50% of patients can have disease that is controlled in the rest of their body, and the CNS remains a sanctuary site. There has been a lot of focus on those drugs to target that.

Also, there is the role of immunotherapy. Having immunotherapeutic strategies where patients can have long-term responses has been a hope and goal of the field. The immediate unmet need is how to treat the patients CNS and entire body.

There are some trastuzumab biosimilars in the mix now. What would the adoption of these agents do for the treatment landscape?

We have made significant progress with drugs that improve how long patients live with HER2-positive breast cancer, but we recognize that there remains an unmet need. With these new drugs, we are hoping to make some significant progress.There is a lot of interest in some studies that are being reported with trastuzumab biosimilars. This does have significant implications, not only in the United States but globally speaking. For countries who don't have access to trastuzumab, a biosimilar could have an impact as there is a differential in cost and access.

Freedman RA, Gelman RS, Melisko ME, et al. TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). J Clin Oncol. 2017;35(suppl; abstr 1005).

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