Novel Advancements Have Led to More Tailored Treatments of Brain Metastases in HER2-Positive Metastatic Breast Cancer

Substantial advancements over the past several years have given rise to a more tailored approach in the treatment of active central nervous system disease — particularly brain metastases — in patients with HER2-postive metastatic breast cancer, according to an expert.

“Macromolecule biologics, such as monoclonal antibodies or antibody-drug conjugates, can penetrate the blood–brain barrier, resulting in objective responses,” Dr. Mark Pegram, an associate dean for Clinical Research Quality at Stanford University School of Medicine in California, said during a presentation at the 39th Annual Miami Breast Cancer Conference®. “(Tukysa)-based therapy improves overall survival for patients with HER2-positive breast cancer with brain metastases, while maintaining overall health-related quality of life, with some potential benefit also seen in leptomeningeal metastasis.”

Exposing Risk Factors

Certain risk factors that are associated with brain metastases in this patient population, according to Pegram, include a triple-negative histology, presence of cancer cells in the lymph nodes, a short time to distant disease relapse and young age.

Another risk factor, however, is HER2 gene amplification/overexpression. There is an approximate four-time greater risk of central nervous system disease in a HER2-positive population, Pegram explained, with brain metastasis appearing in approximately half of those who present with HER2-positive metastatic disease.

Within the HER2 subtype, the SystHERs study of 977 patients further identified an age of less than 50 years, recurrent metastatic breast cancer and hormone-receptor negative status as additional risk factors for central nervous system metastases.

Reducing the Number of Toxicities

Although local therapy (defined as treatment — such surgery, radiation, cryotherapy and laser therapy —directed toward a specific organ or area of the body) is commonly used to treat brain metastases in this population, this method is often associated with side effects, according to Pegram.

However, there are data from a particular phase 3 trial that demonstrated that the use of stereotactic radiosurgery, which avoids the hippocampus (an area of the brain that plays a major role in learning and memory), reduced the negative effects of local therapy when compared with whole-brain radiotherapy (the application of radiation to the entire brain to kill tumor cells).

In these findings, serious or severe cognitive disturbances occurred in 3% of patients who received stereotactic radiosurgery compared with 5% for whole-brain radiotherapy, hearing impairment in 3% versus 9%, respectively, and mild to moderate side effects were 16% and 23%, respectively.

“Brain metastases often occur quickly during the course of HER2-positive metastatic breast cancer, and (that) negatively impacts quality of life and overall survival,” Pegram said. “Local therapy, while effective, does not prevent recurrence and can cause significant toxicities.”

Systemic Therapies for Brain Metastases

The blood-brain barrier has long been a crucial obstacle to developing effective systemic therapies to treat central nervous system disease; however, newer agents have shown signs of overcoming this challenge.

Studies with 89zirconium-trastuzumab (89Zr-trastuzumab) have shown the ability of monoclonal antibodies to cross the blood-brain barrier. In these studies, a high-dose version of Herceptin (trastuzumab) was tested in combination with Perjeta (pertuzumab) for patients with HER2-positive metastatic breast cancer with progressive brain metastases, with promising results demonstrated in the phase 2 PATRICIA study (NCT02536339).

Here, the central nervous system objective response rate (the assessment of the tumor burden following treatment) was 11% and the median duration of response was 4.6 months; the four- and six-month clinical benefit rates were 68% and 51%, respectively.

The HER2-targeted antibody drug conjugate Kadcyla (ado-trastuzumab emtansine) has also shown efficacy in patients with brain metastases and HER2-positive metastatic breast cancer. Objective response rates in this retrospective study were similar between those with brain metastases (35.1%) and for those without (38.3%), demonstrating the efficacy of antibody drug conjugates in this space. Additionally, the disease control rates were 53.3% and 66.6%, respectively.

The data also demonstrated that the median overall survival was 14 months in the patients with brain metastases compared with 32 months in those without.

The ability of antibody drug conjugates to cross the blood-brain barrier to elicit intracranial responses was further demonstrated with Enhertu (fam-trastuzumab deruxtecan-nxki) in the phase 3 DESTINY-Breast03 study (NCT03529110), with intriguing efficacy noted in patients with brain metastases that was superior for Enhertu over Kadcyla.

In data from this pivotal study, the intracranial response rate was 63.9% with Enhertu compared with 33.3% for Kadcyla.

In addition to biologics, the small molecule inhibitor Tukysa (tucatinib), in combination with Herceptin and capecitabine, has also demonstrated efficacy for patients with brain metastases in the HER2CLIMB study (NCT02614794). In this study, the confirmed intracranial objective response rate with Tukysa was 47.3% compared with 20.0% with placebo, Herceptin and capecitabine.

In updated results, this also translated to a marked improvement in progression-free survival (time during and after treatment a patient lives without disease progression) and overall survival.

Based on the HER2CLIMB results, the Food and Drug Administration approved Tukysa in April 2020 for use in combination with Herceptin and capecitabine, for the treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received one or more prior anti–HER2-based regimens in the metastatic setting.

This Tukysa regimen was also explored as a potential treatment for patients with HER2-positive breast cancer and leptomeningeal metastasis, in the phase 2 TBCRC049 study. In data from this trial, 35% of patients remained alive at a median follow-up of 18 months. Moreover, the median overall survival was 10 months and the median time to central nervous system progression was 6.9 months.

“Following taxane, (Herceptin), and (Perjeta) therapy, (Enhertu) is now the preferred regimen for those without central nervous system disease. For those with active central nervous system disease, clearly (Tukysa), (Herceptin), and capecitabine is a strong consideration, because there's level 1 evidence of overall survival benefit with statistical confidence,” Pegram said. “For those with stable central nervous system disease, it is probably more of a toss-up.”

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A version of this story originally appeared on OncLive® as, “Brain Metastases Are Now More Treatable in HER2+ Metastatic Breast Cancer.”