Dr Hamilton on Unmet Needs for Brain Metastases in HER2+ Metastatic Breast Cancer

“Brain metastases are still a big unmet need. We know, particularly in HER2-positive disease, that up to 50% of our patients will have brain metastases at some point in their journey. [However,] we’re learning a lot more. We used to think that antibody-drug conjugates didn’t cross the blood-brain barrier, and now, looking at the activity of trastuzumab deruxtecan, certainly that’s not the case.”

Erika P. Hamilton, MD, the director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, highlighted the unmet needs regarding treatment for brain metastases in patients with HER2-positive metastatic breast cancer.

Although unmet needs remain in several areas in the HER2-positive breast cancer landscape, a significant unmet need includes addressing brain metastases, Hamilton began. Particularly in the HER2-positive breast cancer space, up to 50% of patients will encounter brain metastases at some point, she explained. However, additional research has provided greater context in terms of understanding how to treat brain metastases, she continued. Historically, antibody-drug conjugates were believed not to cross the blood-brain barrier, she noted. Nevertheless, the activity demonstrated by fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) has debunked this original perception, likely due to the altered blood-brain barrier penetration with brain metastases, along with radiation or surgery, she reported.

Furthermore, the phase 3 HER2CLIMB trial (NCT02614794), which evaluated the efficacy and safety of tucatinib (Tuksya) in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab, pertuzumab (Perjeta), and trastuzumab emtansine (Kadcyla), or had brain metastases that did not require immediate local intervention. Of note, the study was one of the first to include patients with untreated brain metastases or those with treated but progressive brain metastases, Hamilton emphasized.

Patients enrolled on the trial were 18 years of age or older with advanced HER2-positive breast cancer; had previously received trastuzumab, pertuzumab, and trastuzumab emtansine; and had an ECOG performance status of 0 or 1. Patients with untreated brain metastases larger than 2 cm in diameter were also permitted with approval from the medical monitor. On the study, patients were randomly assigned 2:1 to receive tucatinib at 300 mg twice daily throughout the treatment period or placebo twice daily, in combination with trastuzumab at 6 mg/kg once every 21 days after an initial loading dose of 8 mg/kg, and capecitabine at 1000 mg/m2 twice daily on days 1 to 14 of each 21-day cycle. Notably, patients were stratified based on brain metastases status, ECOG performance, and geographical region.

Hamilton concluded that she looks forward to seeing more trials that will include patients with brain metastases to further address this unmet need.