Modern Therapies Offer a Way to Reach the Brain in HER2+ Metastatic Breast Cancer

Stephanie Weiss, MD

In HER2-positive breast cancer, the spread of disease to the brain is common, said Stephanie Weiss, MD, but a small proportion of patients die from brain metastases. This ability to survive the metastasis is due to treatments like radiosurgery, which is the current standard of care (SoC) for brain metastases.

New data around tucatinib (Tukysa), which was recently FDA approved in combination with trastuzumab (Herceptin) and capecitabine as treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases who have received one or more prior anti-HER2–based regimens in the metastatic setting, could change the SoC by offering the same capability with one drug that treats the body and the brain, Weiss noted.

The impressive takeaway from the results of the phase 2 HER2CLIMB trial, the study that supports tucatinib’s approval, is that the drug delayed central nervous system (CNS) progression, which has not been accomplished with systemic therapy previously.

In an interview with Targeted Oncology, Weiss, chief of the Division of Neurologic Oncology, and associate professor of the Department of Radiation Oncology at Fox Chase Cancer Center, reviewed the treatment landscape for HER2-positive metastatic breast cancer and gave her predictions on how the paradigm will evolve for patients with brain metastases now that tucatinib has demonstrated efficacy.

TARGETED ONCOLOGY: Can you summarize the treatments available for patients with breast cancer that has metastasized to the brain?

Weiss: The gold standard for patients with metastatic brain disease is radiation. There are a couple of different strategies. Radiation typically involves either treatment focused on individual lesions or it can involve whole-brain radiation therapy (WBRT), which can potentially deal with microscopic or subclinical lesions.

For all patients, some form of radiation typically comes into the picture. Other therapies also have may have a role, like surgery. Surgery is typically done when a patient has a brain metastasis that is causing symptoms that are not relieved with steroids or, for whatever reason, it is believed that the risk of doing radiation alone is too high. Surgery is also done if there is any ambiguity or question about what a [radiation oncologist] is looking at on the MRI.

More recently, there are systemic therapies delivered by a medical oncologist, which have at least some impact on the brain. These therapies are not what would be considered gold standard or ones that should be routinely used as first-line therapies, but there's increasing evidence that if done judiciously, these [drugs] are very helpful. Sometimes, [systemic therapies] can render other therapies as ones that can even lead to a transition from a bigger treatment like WBRT to something that is better tolerated, like stereotactic radiosurgery.

TARGETED ONCOLOGY: What data have we seen recently that is most promising for these patients?

Weiss: I think the most interesting data for patients with brain cancer metastases comes from the HER2CLIMB study and the use of tucatinib for these patients. These are patients with breast cancer that has overexpression of HER2. What’s interesting about this is HER2-positive disease has a predilection to go to the brain, probably because the brain is a sanctuary site from the standard systemic therapies. When therapies were first introduced in the clinic, treatment remained below the neck and got the metastasis under control, but the brain remained a sanctuary from therapy.

With tucatinib, what’s exciting is that we have a drug that we believe is demonstrating some good efficacy in the brain. The HER2CLIMB study is interesting because what they did was enroll patients with metastatic disease, including brain disease, and they looked at progression-free survival (PFS). What they found was that in patients with or without brain disease, tucatinib improved PFS and overall survival.

The first paper in the New England Journal of Medicine didn’t tease out specifically how the brain was responding. But if you look at it in terms of all-comers with metastatic disease, including brain disease, the fact that general PFS was improved in this group suggests that there is a direct impact with the brain. This is something that we’re seeing in the clinic.

Based on the pharmacokinetics that we already know about the drug, HER2CLIMB suggests that the therapy is reaching the brain enough to delay progression within the brain. If it did not do that, we may not see such a powerful difference in general PFS.

The next logical step is, let’s look at the brain specifically to see how tucatinib impacts CNS brain control as an end point.

By having patients in the clinic that I’ve treated, my gut instinct is that we’re going to see that tucatinib suppresses brain metastases, and in other words, it will help prevent new lesions from developing in the brain. This may allow us to transition from the more toxic WBRT to stereotactic radiosurgery.

TARGETED ONCOLOGY: Multiple systemic treatments have demonstrated efficacy for treating brain metastasis. Do you think there is still a role for radiotherapy? What is the current role of surgery?

Weiss: The role of radiotherapy is still there and I think the best way to think about this is to look at it in analogy to what we’ve seen in the past 10 years with lung cancer.

We’ve had these CNS-penetrating drugs like erlotinib (Tarceva) and crizotinib (Xalkori). For certain lung cancers, we’ve been able to defer radiation down the line, or sometimes transition from an aggressive WBRT to a stereotactic radiosurgery approach by using these drugs. I think we’re going to see the same thing in the breast cancer field. Just like with lung cancer, my expectation is that it's not going to change the role for radiotherapy in the big picture. Radiotherapy is still going to be the gold standard in the indefinite future in terms of what is needed to successfully treat.

The way to look at is that these drugs can be suppressive for disease in the brain, which sometimes is good enough but, they’re not going to be ablative in the way that radiation is. I would also say that we’re probably going to use surgery to a more limited extent because surgery is not the gold standard for this.

Surgery has a very particular role. Surgery is used when steroids are not working and if physicians don’t know what they’re dealing with. If you don’t know what you’re dealing with, you’re going to need to get tissue. Also, if a patient has a lesion large enough to cause mass effect, CNS-penetrating drugs are not likely to turn that around.

TARGETED ONCOLOGY: What are the ongoing questions with regards to eliminating brain tumors in patients with breast cancer?

Weiss: An interesting question in this space is what it means for a patient to have brain metastases. It’s important to understand that a very small population of patients die from brain metastases.

Having a new therapy for brain metastases is going to help improve the quality of life and lead to fewer situations where patients are dealing with CNS progression or at least not as soon as they have been. I also think a large factor here is what new therapy can do for limiting radiation by delaying radiation. There’s an advantage to having a drug that can treat the body and the brain. That’s advantageous because if you get the same thing with one therapy, you don’t have to worry about the toxicities of another therapy.