HER2CLIMB Regimen Explored in HER2-Breast Cancer with Leptomeningeal Metastases

Debasish Tripathy, MD

The combination of tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine (Xeloda) has shown to be effective in the treatment of HER2-positive breast cancer with leptomeningeal metastases. However, questions remain over whether the combination crosses the blood-brain barrier.

According to Debasish Tripathy, MD, professor and chairman of the Department of Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, up to 50% of patients with HER2+ breast cancer will develop leptomeningeal metastases.

The 049 study (NCT03501979), which has an estimated enrollment of 30 participants, aims to determine if the triplet combination is effective in treating leptomeningeal disease. It consists of a single arm and all patients received the combination. According to Tripathy, preliminary evidence suggests the combination is effective in penetrating the spinal fluid. 

In an Interview with Targeted Oncology, Tripathy discusses the triplet regimen for HER2+ breast cancer with leptomeningeal metastases in greater detail along with its broader clinical applications.

TARGETED ONCOLOGY: Can you give me an overview of what you presented at the American Society of Clinical Oncology's Annual Meeting this year?

TRIPATHY: This is the TBCRC049 study, which is a study assessing the use of tucatinib, capecitabine, and trastuzumab for patients with HER2-positive leptomeningeal central nervous system [CNS] involvement. This is a unique study in that we are not only looking at the efficacy of this novel combination, which already has been shown to have activity in brain metastases, but we're also doing pharmacokinetic studies, which are generally very difficult to do. We want to basically see if the drug enters into the cerebral spinal fluid. And what its time course over time is, both in the blood as well as what percentage of it makes it into the cerebral spinal fluid.

What data lead up to this study?

The initial thinking of the study was that patients with HER2-positive breast cancer do have a fairly high incidence of developing brain metastases. In patients with metastatic HER2- positive disease, as many as 50% of patients over some course of their treatment are going to experience brain metastases and in some cases, this involves a particularly aggressive form of this known as leptomeningeal disease, which involves the minigenes and typically, one sees positive cancer cells in the cerebrospinal fluid. This tends to have an even worse prognosis then intracranial metastasis.

So, in the HER2CLIMB (NCT02614794) study, which was the randomized study that led to the approval of the addition of tucatinib to the backbone of capecitabine and trastuzumab was tested in patients with metastatic breast cancer, and it allowed patients with brain metastases, and even allowed patients with untreated brain metastases, who did not receive local treatment but had minimal symptoms. So overall, about half the patients in that study had brain metastases. The results of that study did show that the addition of tucatinib improved progression free and overall survival. And in particular, it improved these outcomes in patients with brain metastases. In the patients that have untreated brain metastases, they actually saw responses in that group of patients. So that study, as well as studies that had preceded the randomized study, because even in the phase one study of tucatinib, patients with brain metastases were seen to have responses. So that really led to this TBCRC study, to test it in a smaller group of patients that have leptomeningeal disease that is HER2-positive.

What was the study design?

The study design was to enroll patients with newly diagnosed leptomeningeal disease. These are patients who were diagnosed and confirmed either by imaging or by cerebral spinal fluid positivity to have leptomeningeal involvement, those patients were eligible, and they underwent complete neuro access imaging, they underwent examination, both for standard of care as well as research studies, including drug levels of their cerebral spinal fluid. And they were treated with tucatinib, trastuzumab, and capecitabine according to the FDA approved regimen, and they were treated as long as they did not have clinical or radiographic progression, or intolerable side effects of therapy.

What concentration levels have you observed?

This was a study primarily looking at the concentrations in the blood and in the cerebral spinal fluid. We reported here, the cerebral spinal fluid concentrations, and the results of the outcomes, the primary outcomes, which are response rate and time to progression will be reported later because the patients are still being followed. This particular poster was to look at the cerebrospinal fluid concentrations. We showed that the patients did achieve concentrations that were in the range of 0.5 ng/ml, which is an active range, in vitro, at least, and these were maintained over time. These types of numbers really haven't been described over time, with many drugs. And so, the concentrations range from point 0.2 to 4.7 ng/ml. Then, we also looked at the CSF to plasma ratios, you know, what percent of the drug is actually getting through. And the ratios ranged from 0.8 in cycles 1 and 2, which is when we measured them, from 0.18 to 4.0, with a median of 0.87. And they did not really appear to fluctuate very much over time.

Do you think this research will be applicable to other cancer types where the disease is metastatic?

There are studies going on and other types of cancers that are HER2-positive. for example, gastric cancer is known to have a 205 to 25% positivity of HER2, and HER2 agents are in fact approved in HER2-positive gastric cancers. But now that we're doing next generation sequencing on a broader number of patients were finding that either amplification or activating mutations can be found in HER2 in a very broad range of tumors. We're seeing them in lung cancers, colorectal cancers, and bladder cancers. And even in hormone receptor positive and HER2-negative cancers, we're starting to see some patients that develop mutations in HER2, particularly patients who have hormone receptor positive breast cancer and have been exposed to endocrine therapy. So, we now test our patients for mutations in HER2, because these are cases where the standard HER2 amplification and immunohistochemistry is negative. It's not presents in high amounts, but the small amount that is present is mutated and turned on. And we now know that these cases can respond to kinase inhibitors like neratinib (Nerlynx), and more recently have shown that if they're hormone receptor positive, we actually get better results if you combine it with endocrine therapy like fulvestrant (Faslodex). And then most recently, even better results if you combine it with trastuzumab. So, the way we approach multiple diverse tumors that are HER2-positive, either on the basis of amplification or mutation, is changing. And these are patients who many of them can stand to benefit from HER2 targeted agents. And similarly, for patients who develop brain metastases from these tumors, they may benefit from the drugs that are known to cross the blood brain barrier.

What is the status of this study? Do you have any future research planned in this space?

So of course, we want to complete this particular study so that we can define what tucatinib containing regimens can do for leptomeningeal disease, and there are other studies looking at brain metastases as well. We are looking at different ways to treat HER2-positive breast cancers on the basis of mutations, as I mentioned, using things like antibody drug conjugates. that's another area where we've seen major improvements in the treatment of HER2-positive disease. For example, the antibody drug conjugate known as trastuzumab deruxtecan (Enhertu), has shown dramatic results. Not only in HER2-positive patients, but also in HER2-low, patients that are technically HER2-negative, but express it at a level of 1-2+, but without amplification of the gene. So, this is a very exciting area where we can actually treat HER2-low. There have been some patients with CNS disease that have responded to this agent, even though it's an antibody-based agent, which are large and are thought not to penetrate the blood brain barrier very well, we are seeing a response. So, there are several studies now looking at this particular antibody drug conjugate as well as others for HER2-positive brain metastases.

One of the big controversies in the field, because patients with advanced HER2-positive breast cancer develop brain metastases at such a high rate, is should they be screened automatically for brain metastases if they're not symptomatic? This is not something we typically do. We don't obtain a brain MRI unless there's symptoms, and we don't even know if it's helpful to pick patients up very early before they need treatment, because it's possible that some of these patients may do fine with systemic therapy. But once we know they have brain metastases, we monitor them, we treat everything that shows up with stereotactic radiation, or even whole brain radiation. We may, in fact be over treating these patients. On the other hand, it's very disturbing when you have a patient that has advanced breast cancer, and they present with a seizure as their first manifestation of a brain metastases. And many of them actually asked, well, should I have had screening of my brain? And you say, 'well, no, that's not the standard of care, and we're still studying it.' But it really begs the question whether we should be doing it. So, there are some pilot studies that are actually going on now to go ahead and get a brain MRI and follow the outcomes of these patients so we can better characterize that. It may very well be that these kinds of studies lead to a change in in this paradigm that we've had for a very long time as to not to screen the brain unless there's symptoms.

I think it's really important for everybody to understand that the new era of cancer treatments requires a very close tie to examining what's going on in the tumor in real time. Not only do we learn how to better treat, and personalize treatment for our patients, and to de-escalate therapy when needed, and to escalate therapy when we need to. But it's giving us more insights into the basic biology of cancer and what drives drug resistance, what drives metastases and our ability to develop new targeted therapies from that basic science knowledge. There's a huge amount to be gained by doing correlative studies. We should always be encouraging our patients to participate in studies, even when they may require things like extra biopsies, because it is helping our field accelerate so quickly. So really, you should be looking forward to seeing many more interesting novel therapies that are linked to biomarker testing that is very elucidating. We really think this is going to accelerate how we move towards personalized and more effective therapies.

_REFERENCE:

_{Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD. ClinicalTrials.gov. Accessed August 26, 2021. https://bit.ly/2UQMFRb.}