ONCAlert | Upfront Therapy for mRCC

Unmet Needs in R/R HER2+ Metastatic Breast Cancer

Targeted Oncology
Published Online:12:00 PM, Fri July 19, 2019

Adam M. Brufsky, MD, PhD: The needs for women with third-line and beyond metastatic breast cancer are unclear. We know that in the first line, we give most people taxane, trastuzumab, pertuzumab, and we know a lot of women in the second line get trastuzumab emtansine, TDM1. After those 2 though, we don’t really have a good idea of what to do. Lapatinib and capecitabine is an option for women with brain metastases. But generally, what we do is we give people anti-HER2 [human epidermal growth factor receptor 2] therapy, usually trastuzumab, plus a number of different chemotherapies. And I think that of the unmet needs, what we do about brain metastases is probably the biggest one. At least 50% to 60% of women at some point in their disease course, will develop metastatic disease to the brain.

I think we do such a good job of treating their systemic disease with anti-HER2 therapy that this is what they eventually die from. And in fact, what tends to happen that’s even worse is that we’ll treat their brain metastases with stereotactic radiation for a number of times, and eventually go to whole brain radiation. And women do so well now from their systemic disease, the vast majority—I wouldn’t say everybody—eventually will have systemic progression. But I have a lot of women now in my practice who actually die from the complications of the whole brain radiation. People are living long enough now, and 2, 3, 4 years later develop dementia. Now they have hippocampal sparing radiation, but still it’s not perfect. And oftentimes you have to reradiate the brain.

So I think that things that address areas of HER2 resistance, things that penetrate the CNS [central nervous system] and actually maybe delay the onset of progression of existing brain metastases, are the things that we need to do to make the next big steps in this disease.

Regarding CNS metastases with HER2-positive disease, I think metastatic disease, especially in the second-, third-, fourth-, fifth-line setting, is the dominant thing that can affect your quality of life as well as your survival. And again, the agents that are most effective—trastuzumab, pertuzumab, TDM1—really generally can’t penetrate the CNS, and we’ve had this whole debate about whether the blood brain barrier is disrupted and these agents can get there.

But I think we understand, and we all have the situation where a woman will have a tremendous systemic response, a CR [complete response] to all of her disease, but 2, 3, 4 years later will develop metastases to their brain. That tells you that that therapy isn’t getting in and the micrometastases are developing to symptomatic macrometastases. And I think that this truly is the big issue right now. There are several. But obviously 2 of the big things are developing agents that really prolong systemic response, but more importantly, developing agents that actually penetrate the CNS and can treat it.

How do existing regimens meet the unmet medical need? Unfortunately, a lot of them don’t. I think that the large antibodies, or large molecules, don’t penetrate the CNS. They don’t get into the CNS. We have lapatinib, which does get into the CNS to some degree, but it’s a reversible agent so basically it doesn’t really accumulate in the CNS, it comes right back out. You can’t really get therapeutic levels, and if you do, the effect on the HER2 tyrosine kinase is transient. So we need better agents that get in and that can synergize with whatever systemic therapy we can get into the CNS.

Transcript edited for clarity.

Adam M. Brufsky, MD, PhD: The needs for women with third-line and beyond metastatic breast cancer are unclear. We know that in the first line, we give most people taxane, trastuzumab, pertuzumab, and we know a lot of women in the second line get trastuzumab emtansine, TDM1. After those 2 though, we don’t really have a good idea of what to do. Lapatinib and capecitabine is an option for women with brain metastases. But generally, what we do is we give people anti-HER2 [human epidermal growth factor receptor 2] therapy, usually trastuzumab, plus a number of different chemotherapies. And I think that of the unmet needs, what we do about brain metastases is probably the biggest one. At least 50% to 60% of women at some point in their disease course, will develop metastatic disease to the brain.

I think we do such a good job of treating their systemic disease with anti-HER2 therapy that this is what they eventually die from. And in fact, what tends to happen that’s even worse is that we’ll treat their brain metastases with stereotactic radiation for a number of times, and eventually go to whole brain radiation. And women do so well now from their systemic disease, the vast majority—I wouldn’t say everybody—eventually will have systemic progression. But I have a lot of women now in my practice who actually die from the complications of the whole brain radiation. People are living long enough now, and 2, 3, 4 years later develop dementia. Now they have hippocampal sparing radiation, but still it’s not perfect. And oftentimes you have to reradiate the brain.

So I think that things that address areas of HER2 resistance, things that penetrate the CNS [central nervous system] and actually maybe delay the onset of progression of existing brain metastases, are the things that we need to do to make the next big steps in this disease.

Regarding CNS metastases with HER2-positive disease, I think metastatic disease, especially in the second-, third-, fourth-, fifth-line setting, is the dominant thing that can affect your quality of life as well as your survival. And again, the agents that are most effective—trastuzumab, pertuzumab, TDM1—really generally can’t penetrate the CNS, and we’ve had this whole debate about whether the blood brain barrier is disrupted and these agents can get there.

But I think we understand, and we all have the situation where a woman will have a tremendous systemic response, a CR [complete response] to all of her disease, but 2, 3, 4 years later will develop metastases to their brain. That tells you that that therapy isn’t getting in and the micrometastases are developing to symptomatic macrometastases. And I think that this truly is the big issue right now. There are several. But obviously 2 of the big things are developing agents that really prolong systemic response, but more importantly, developing agents that actually penetrate the CNS and can treat it.

How do existing regimens meet the unmet medical need? Unfortunately, a lot of them don’t. I think that the large antibodies, or large molecules, don’t penetrate the CNS. They don’t get into the CNS. We have lapatinib, which does get into the CNS to some degree, but it’s a reversible agent so basically it doesn’t really accumulate in the CNS, it comes right back out. You can’t really get therapeutic levels, and if you do, the effect on the HER2 tyrosine kinase is transient. So we need better agents that get in and that can synergize with whatever systemic therapy we can get into the CNS.

Transcript edited for clarity.
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