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MIAMI BEACH -- Newer therapies for HER2-positive breast cancer have started to overcome blood-brain barrier (BBB) obstacles to offer more effective therapy for brain metastases, according to a review presented here.

Monoclonal antibodies, antibody-drug conjugates (ADCs), and certain targeted agents have demonstrated activity against intracranial metastases. The brain-specific activity has been associated with improved quality of life (QoL) and longer survival, said Mark Pegram, MD, of Stanford University School of Medicine in California, at the Miami Breast Cancer Conference.

"Local therapy, while effective, does not prevent recurrence [of brain metastases] and can cause significant toxicities," he said. "Macromolecule biologics, such as monoclonal antibodies and ADCs, can penetrate the BBB, resulting in objective responses. Tucatinib (Tukysa)-based therapy improves overall survival [OS] for patients with HER2-positive breast cancer brain metastases while maintaining overall health-related QoL and may include some potential benefit in leptomeningeal disease."

"Screening guidelines that recommend screening for CNS [central nervous system] metastases only in symptomatic patients may not adequately capture all patients with brain metastases. If your treatment decision will be affected by whether or not the patient has brain metastases, MRI could be indicated even in asymptomatic patients," he added.

Defining the Problem

A recent confirmed that HER2 amplification or overexpression as a major risk factor for development of breast cancer brain metastases. About half of patients with metastatic HER2+ breast cancer develop brain metastases, and the incidence has increased in recent years. The review also showed that breast cancer brain metastases are associated with triple-negative disease, tumor grade, increased Ki-67 expression, nodal involvement, number of metastatic sites, shorter time to distant relapse, larger tumors, and younger age.

A limited to patients with metastatic HER2+ breast cancer showed an increased risk of brain metastases in patients younger than age 50, recurrent metastatic disease, and hormone receptor-negative status.

A study of for patients with metastatic HER2+ breast cancer showed a from the onset of brain metastases. A of lapatinib (Tykerb) and capecitabine for untreated HER2+ brain metastases showed a time to progression/progression-free survival of 3.5 to 5.5 months. A study of patients with HER2+ breast cancer and CNS metastases showed a within 2 years of metastasis diagnosis, and metastasis progression was the cause of death in 70% of the cases.

Historically dismal outcomes in HER2+ breast cancer brain metastases owe in large part to the inability of conventional chemotherapeutic agents to penetrate the BBB, said Pegram. Local therapy (primarily radiation but also surgery in select cases) can be helpful but may have serious adverse effects (particularly cognitive disturbance), even with newer targeting and delivery techniques. Moreover, local therapies do not prevent future CNS progression.

Therapeutic Breakthrough

Surprisingly, large molecular-weight antibodies have accomplished what light-weight therapeutic antibodies could not: penetrate the BBB. In a , 37 patients with metastatic HER2+ breast cancer and brain metastases received high-dose trastuzumab (Herceptin) plus pertuzumab (Perjeta) in the post-radiotherapy setting. Several patients achieved objective responses in the brain, and a majority of patients had some degree of reduction in brain metastasis volume. Some of the responses were durable, lasting for as long as 30 months.

"I thought this was fairly intriguing," said Pegram. "It established proof of concept that therapeutic antibodies can provide some measure of response in HER2-positive breast cancer brain metastases, and it opens up the door for future antibody therapeutics, as well as ADCs."

Ongoing development of HER2-targeted ADCs has confirmed the ability of the therapeutic class to achieve meaningful and durable activity in brain metastases. In a study of 53 patients with HER2+ metastatic breast cancer and brain metastases, the ADC (T-DM1, Kadcyla) achieved an intracranial response rate of 30.2%, which compared favorably with the 35.1% extracranial response rate and 38.3% in patients without brain metastases.

More recently, the ADC trastuzumab deruxtecan (T-DXd, Enhertu) set a new benchmark for clinical activity in metastatic HER2+ breast cancer, leading to more than a two-fold improvement in 12-month progression-free survival (PFS) versus T-DM1. In the subgroup of patients with brain metastases, T-DXd achieved an intracranial objective response rate of 63.9% versus 33.4% with T-DM1. More than a fourth of the patients in the T-DXd arm had complete responses in the brain.

The small-molecule inhibitor tucatinib has further expanded treatment options for HER2+ brain metastases when used in combination with trastuzumab and capecitabine. In the HER2CLIMB randomized trial, the three-drug combination led to an intracranial objective response rate of 47.3% as compared with 20.0% for the trastuzumab-capecitabine doublet.

Among patients with active brain metastases, the addition of tucatinib was associated with a 9-month improvement in median OS (20.7 vs 11.6 months) and almost a 50% improvement in new brain lesion-free survival. CNS-PFS more than doubled with tucatinib for patients with active or stable brain metastases.

HER2CLIMB also showed no deterioration in QoL in patients who received the tucatinib-containing triplet and was superior to QoL in the control group.

"That's what treatment of brain metastases is all about, maintaining QoL and survival," said Pegram.

Most recently, the tucatinib-trastuzumab-capecitabine regimen demonstrated meaningful improvement in patients with metastatic HER2+ breast cancer and leptomeningeal metastasis. A of patients with newly diagnosed leptomeningeal metastasis showed a median OS of 10 months versus 4 to 5 months for a historical control group, representing the first prospective evidence of clinical benefit in HER2+ leptomeningeal metastasis with systemic therapy.

The recent developments in managing HER2+ brain metastases have shuffled the treatment flowchart.

"Following taxane and dual-antibody [trastuzumab and pertuzumab] therapy in first line, T-DXd is now the preferred regimen for patients without brain metastases," said Pegram. "For those with active CNS disease, clearly, the tucatinib-trastuzumab-capecitabine regimen is a strong consideration because there is level one evidence of an OS benefit from a randomized, phase III trial. For those with stable brain metastases, it's probably more of a toss up."

With the emergence of more effective therapies for brain metastases, clinical guideline committees may need to revisit recommendations for screening for brain metastases in patients with metastatic HER2+ breast cancer, he added. Current guidelines generally recommend screening only for symptomatic patients. That approach might not adequately capture all the patients who could benefit from treatment.

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