Dr McCann on the Treatment Paradigm for HER2+ Breast Cancer With Brain Metastases

“The big challenge in treating patients with HER2-positive breast cancer is that they can develop brain metastases later on, and this is challenging because we don’t have a lot of therapies that cross the blood-brain barrier.”

Kelly E. McCann, MD, PhD, assistant professor, breast medical oncologist, UCLA, discusses current and evolving treatment strategies for patients with HER2-positive breast cancer who develop brain metastases.

A major challenge in the management of HER2-positive breast cancer is the development of brain metastases, which are a therapeutic hurdle due to the limited ability of many systemic agents to cross the blood-brain barrier, McCann begins. HER2-targeted TKIs—including pan-HER inhibitors like neratinib (Nerlynx)—have demonstrated intracranial activity, she says.

Additionally, the phase 2 HER2CLIMB trial (NCT02614794), which evaluated the efficacy of tucatinib (Tukysa) in combination with trastuzumab (Herceptin) and capecitabine in previously treated patients with HER2-positive metastatic breast cancer, uniquely included a significant proportion of patients with brain metastases, a population often excluded from clinical trials, she explains. An exploratory subgroup analysis of this trial showed that at a median follow-up of 29.6 months (range, 0.1-52.9), among the 291 patients with brain metastases (47.5% of the total study population), the tucatinib-based regimen led to a median overall survival of 21.6 months (95% CI, 18.1-28.5) vs 12.5 months (95% CI, 11.2-16.9) with placebo plus trastuzumab and capecitabine. Moreover, the duration of intracranial response was 8.6 months (95% CI, 5.5-10.3) in the tucatinib arm vs 3.0 months (95% CI, 3.0-10.3) in the placebo arm.

Furthermore, emerging data indicate that fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) may also penetrate the blood-brain barrier, according to McCann. Its proposed mechanism of action involves the intracellular release of its cytotoxic payload, which may then diffuse across the blood-brain barrier, as opposed to the full antibody-drug conjugate itself crossing intact, she notes. Therefore, T-DXd is a potential therapeutic strategy for patients with HER2-positive breast cancer with brain metastases, and warrants further investigation in this population, she concludes.