Novel Combination Strategies in HER2+ Metastatic Breast Cancer With CNS Disease

Comprehensive review of novel combination treatment strategies being explored for patients with HER2+ breast cancer and brain metastases.


Sara Tolaney, MD:Tell us a little about what we might see in the future for T-DXd [trastuzumab deruxtecan] with brain metastases in a large study. You’re involved in helping lead, which hopefully will give us more data.

Nancy Lin, MD: DESTINY-Breast12 is a global study, and it’s designed with 2 cohorts. One cohort is patients without brain metastases, looking in the second- and third-line settings in a larger group of patients globally. The cohort that’s most interesting is the brain metastases cohort, which will enroll up to 250 patients with brain metastases. This is getting more along the same lines of the sample size of HER2CLIMB. That study will allow patients with both active and stable brain metastases to enroll. The study is enrolling and will provide us with important prospective data in a large set of patients. This allows us to fill in the gaps that we have.

Sara Tolaney, MD:That will be exciting to see in a large number of patients. There are lots of other drugs also being investigated. Sarah, you can tell us about some of the novel approaches being considered.

Sarah Sammons, MD: The field is going to continue to evolve. T-DXd [trastuzumab deruxtecan] is being explored in the first-line setting. It’s also being explored in the neoadjuvant and adjuvant setting. Tucatinib is also being explored in all those settings as well. We have HER2CLIMB-02, and we’ll see the results at San Antonio [Breast Cancer Symposium] or ASCO [American Society of Clinical Oncology Annual Meeting] this year. That [study] is tucatinib added to T-DM1 [trastuzumab emtansine] in the second-line setting, with a randomization to tucatinib and T-DM1 [trastuzumab emtansine] vs T-DM1 [trastuzumab emtansine]. Those results will be exciting. Looking at the brain metastases end points in that trial will also be exciting. Tucatinib and trastuzumab deruxtecan are also being combined in a single-arm trial, HER2CLIMB-04, which looks mostly at safety and activity. That’s a single-arm trial that’s enrolling. Then we have HER2CLIMB-05, which is looking at tucatinib added to HP [trastuzumab, pertuzumab] in the first-line setting. Mostly because of tucatinib’s intracranial activity and my interests, I’m very excited by the brain metastases prevention and end points in those trials. There’s an array of new HER2-targeted ADCs [antibody-drug conjugates] and tyrosine kinase inhibitors that are also in the pipeline.

Sara Tolaney, MD:It’s nice to see so much progress being made, and it sounds like more to come. Nancy, if you were a practitioner in the community who has to manage lots of different diseases, I don’t know how they do it. Could you explain how you think about managing patients who have HER2 [human epidermal growth factor receptor 2]–positive brain metastases? Whether it’s stable or active, what do you think is a good take-home message for them?

Nancy Lin, MD: I’ll point to 2 concepts. One is local therapy vs systemic therapy, and 1 is about systemic therapies. These are patients who unfortunately will run through both tucatinib and T-DXd [trastuzumab deruxtecan], and you’re wondering what is the next thing to do. The NCCN [National Comprehensive Cancer Network] has guidelines for systemic therapy for patients with HER2+ as well as HER2- brain metastases, though they’re not found in the breast cancer guidelines. They’re found in the CNS [central nervous system] tumor guidelines. You have to look under the brain metastases subset of the CNS tumor guidelines. They’re hard to find, but they’ve listed a number of regimens, including T-DM1 [trastuzumab emtansine] or high-dose IV [intravenous] trastuzumab with pertuzumab for left meningeal disease. There’s also intrathecal trastuzumab, so there are a number of other regimens that can be considered in the later-line setting along with references of where the data come from. That’s a very useful reference.

The concept related to choice of therapy is important. This idea of brain metastases velocity, which was coined by radiation oncology, is important. After somebody has had initial SRS [stereotactic radiosurgery], how many additional brain metastases are they developing per year after that SRS? It makes sense that if you develop more rapidly, there’s a shorter time and a higher chance for salvage brain radiation therapy. There’s shorter overall survival. That’s also a very useful concept. If a patient has SRS on HP [trastuzumab, pertuzumab] and has 2 lesions, and then they have SRS and, 1½ years later, 3 lesions that are small, I’m likely to send them to radiation oncology and ask them to reradiate those lesions. If a patient has a 3-month scan post-SRS and has 6 new metastases, it doesn’t feel that satisfying to SRS 6 additional lesions 3 months later. For that patient, I might more likely switch their systemic therapy because I’m hoping to treat what I can see and what we can’t see.

Sara Tolaney, MD:That’s very helpful—to think about the velocity and how it may help frame treatment decisions. That was a great overview.

Transcript edited for clarity.

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