Updates in the Treatment of HER2+ and HER2-Low Breast Cancer - Episode 10

Novel Treatment Approaches to Brain Metastases in HER2+ Breast Cancer

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Focusing on the management of brain metastases in HER2+ metastatic breast cancer, panelists share trial data on tucatinib and trastuzumab deruxtecan.


Andrew Seidman, MD: Not at this [ASCO Annual] meeting, but in San Antonio… there was an update of the HER2CLIMB study in terms of durability of benefit in the brain metastases population. Maybe you can speak to tucatinib’s record in metastatic disease and specifically in the brain metastasis population.

Tiffany Traina, MD: Happy to. HER2CLIMB, just to remind everybody, was a randomized study of capecitabine/trastuzumab vs capecitabine/trastuzumab/tucatinib, an oral tyrosine kinase inhibitor against HER2. The HER2CLIMB study actually enrolled patients with metastatic disease, of which about half of those women had brain metastases and quite impressively almost another half of those patients had untreated brain metastases—generally a population we would have excluded from participation in clinical trials. What was really wonderful to see is that the patients receiving the triplet tucatinib plus capecitabine and trastuzumab had improved overall survival, and that included the population with brain metastasis. That benefit has been quite durable; there are not only responses, but also improved progression-free survival and improved overall survival for the overall study population, as well as those patients with brain metastasis.

Andrew Seidman, MD: Right, and then there is this distinction between treated and untreated, and it seems like there is benefit in both groups.

Tiffany Traina, MD: Exactly. We don’t have a radiation oncologist with us today, but it raises the question about when we need local intervention with radiation and is there is an opportunity to use a very effective systemic therapy that crosses the blood-brain barrier and may be able to delay time to [the] need for radiation.

Andrew Seidman, MD: I think we’ll have an opportunity to [answer] the questions for which we don’t have randomized trials like ADCs (antibody-drug conjugates) vs the HER2CLIMB regimen, but before we get there, maybe you can also tell us what we know and we don’t know yet about trastuzumab deruxtecan and CNS [central nervous system] involvement.

Tiffany Traina, MD: Sure. [There is] much more limited data in that setting, but I think historically we have thought bulky antibody-drug conjugates would fail to have a benefit in the CNS. There has been suggestion of benefit from agents like T-DM1 (trastuzumab emtansine), and with trastuzumab deruxtecan, there was a small study, the TUXEDO trial, that enrolled about 15 patients or less than 20 patients with CNS metastasis, and there was a CNS response in about 5 out of 6 patients that were evaluable. So [that was] a signal that there is activity there. Also, there has been a report out of a subset of patients from DESTINY-Breast01, the original phase 1/phase 2 [trial] of trastuzumab deruxtecan, and in about a couple dozen patients with CNS disease, there was CNS response that was quite high—of around 50% as well.

Andrew Seidman, MD: Certainly small numbers, but some interesting signal that there can be CNS efficacy. This is the place where I will do my infomercial to note that this has been an interest of mine. [I] and Shanu Modi [,MD,] are both about to, with our neurosurgical colleagues, embark on an effort to try to understand molecular mechanisms underlying resistance in the brain for patients who need to have craniotomies. We will be doing a very deep dive into the biology, and hopefully that will take us someplace else in a few years.

Transcript edited for clarity.