Defining Value for the Treatment of Brain Metastases in Metastatic HER2-Positive Breast Cancer - Episode 6

Managing At-Risk Patients for Brain Mets in HER2+ mBC

The goals of therapy and unmet needs for patients with HER2-positive metastatic breast cancer at risk for brain metastases are examined.

Sarah Sammons, MD: What are the goals of treatment for patients who are at risk for developing brain metastases? In HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer, all patients are at risk for developing brain metastases, and we treat them all the same until they develop a brain metastasis.

Kevin M. Kalinsky, MD, MS: Our goals of therapy in patients who have brain metastases and HER2-positive pretreated disease is first to improve symptoms. Quality of life is important. Whenever I have a patient with metastatic disease, we talk about how this is not a sprint but a marathon. When one phrases it like that, it’s about keeping things under control and making sure that this person has a good quality of life. That’s our goal.

Our goal is also to keep things under control so that patients have fewer symptoms. If we have stability of disease or, even better, a reduction of disease, then patients often feel better. If they have CNS [central nervous system] metastases, they may have fewer adverse effects. The other important aspect is improving overall survival. If a patient lives longer because we’re giving them therapy, then that can be a game changer.

Sarah Sammons, MD: There are still unmet needs in treating patients with HER2-positive brain metastasis. Historically, these patients were excluded from clinical trials of novel drugs in development. We’ve seen a change since both ASCO [American Society of Clinical Oncology] and the FDA have encouraged a push to include patients with brain metastasis early on in the drug development process. Tucatinib did a good job and was a good example of that for investigators moving forward. They included patients with progressive and untreated brain metastases in their early phase design. They then included patients with not only a history of brain metastases but untreated and progressive brain metastases as well, which we have never seen included in their phase 3 design. That only strengthened the results, strengthened their approval, and made it more appealing for clinicians to prescribe that drug for their patients as 50% of patients with HER2-positivemetastatic breast cancer will develop brain metastasis. Historically, these patients were excluded from clinical trials. That certainly led to their inferior outcomes, but I am seeing a big push for a change in that, and I am very hopeful and excited about that. It will only narrow the gap of outcomes for those patients.

Another challenge in drug development for breast cancer to brain metastases is the lack of preclinical models. I know a lot of preclinical investigators are working hard to overcome that, but that has historically been a challenge because that is how we understand preclinically if a drug works. Additionally, the blood-brain barrier, which is the layering around the brain and allows pharmacological drug entry into the brain, has been challenging. Large bulky molecules, such as monoclonal antibodies and potentially antibody-drug conjugates, have limited perfusion through the blood-brain barrier, whereas smaller compounds such as tyrosine kinase inhibitors have superior penetration, so that has also been a challenge historically.

Kevin M. Kalinsky, MD, MS: In HER2-positive disease, the unmet need is clearly to improve how we treat patients with CNS metastasis as well as preventing CNS metastases in patients with early stage breast cancer. Although we have active agents like the monoclonal antibodies, those don’t offer great CNS control universally. We would like to have agents that we know can treat this disease. We have a number of molecules, but we could absolutely increase the number of agents that we have to treat the disease.

Bhavesh Shah, RPh, BCOP: We’ll want to talk about the unmet needs. We know that historically, clinical trials exclude patients with brain metastases. Why is that? Brain metastasis leads to a poorer outcome, so if you’re trying to do a clinical trial, you want to exclude those patients because you’re testing it in the patients who don’t have brain metastases. You don’t want to influence the results because you have a poor-risk patient population in your clinical trial.

The other issue is that we don’t have many agents that can treat CNS disease. We know cytotoxic chemotherapy does not cross the blood-brain barrier. We have monoclonal antibodies, such as trastuzumab or pertuzumab, and we know that they do not cross the blood-brain barrier. Even T-DM1 [trastuzumab emtansine], which is an antibody-drug conjugate, does not cross the blood-brain barrier well. Not having treatments and knowing that these treatments are not going to cross the blood-brain barrier, these patients were always excluded historically.

However, we’re seeing more clinical trials where they’re allowing patients with asymptomatic and stable brain metastasis. There are definitely agents for which we may see benefit in these patients.