New Combination Regimens Show Promise in Patients with Breast Cancer and Central Nervous System Metastases

In 20 BC, Augustus Caesar said, “All roads lead to Rome.” And between the 1950s and 2010, all roads led to whole-brain radiation for patients with breast cancer and brain metastases, according to Priscilla Brastianos, MD, Director, Central Nervous System Metastasis Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Approximately 30% of patients with advanced breast cancer develop brain metastases, and the incidence is rising as systemic therapies are improving. “Importantly, patients will often develop progressive brain metastases in the setting of stable extracranial disease,” said Dr Brastianos at the 37th Annual Miami Breast Cancer Conference.

Although whole-brain radiation was the standard of care in the United States for more than 50 years, newer data have shown that many patients develop significant neurocognitive decline after whole-brain radiation.

As patients are now living longer, effective therapies to improve standard of care are urgently needed, she said, and one such option is systemic therapy.

“Unfortunately, there are a limited number of prospective trials [of systemic therapies] in brain metastases patients,” Dr Brastianos said. “Most clinical trials exclude patients who have active brain metastases, so while there are smaller studies, many are underpowered. Many reports also include a variety of tumors, which makes it hard to create standard of care for patients when we don’t have a plethora of trials to help guide us.”

Furthermore, most patients with brain metastases have already progressed on several therapies, so these are challenging tumors to treat.

However, according to Dr Brastianos, newer studies of systemic therapies in patients with HER2-positive breast cancer and brain metastases are showing greater promise, and 2 drugs to watch are tucatinib and neratinib (Nerlynx).

Tucatinib is an oral, small-molecule tyrosine kinase inhibitor that is highly selective for HER2. A recent clinical trial evaluated the safety and efficacy of tucatinib or placebo, in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) in patients with HER2-positive metastatic breast cancer. At 1 year, progression-free survival in patients with brain metastases (a secondary end point of the study) was 25% in the tucatinib arm versus 0% in the placebo arm (P <.001). “So, there is a lot of promise with tucatinib in brain metastases,” Dr Brastianos said.

Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has also shown promise in patients with HER2-positive brain metastases. In a phase 2 trial of patients treated with neratinib plus capecitabine, the central nervous system overall response rate was 49%, with a median progression-free survival of 5.5 months. “This is also quite promising,” she noted.

According to Dr Brastianos, systemic therapy for patients with brain metastases should be considered in the frontline setting if patients have multiple asymptomatic brain metastases, and if there is a known effective therapy in that setting. In the recurrent setting, systemic therapy should be considered as a treatment option only after failure of radiation and/or surgery.

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