New drugs for HER2-positive breast cancer are able to overcome some of the obstacles that have made brain metastases challenging to treat, according to Mark Pegram, MD, the Susy Yuan-Huey Hung Professor of Oncology at Stanford University School of Medicine in California, who described the promising treatment landscape at the 2022 Miami Breast Cancer Conference.1
Specifically, some monoclonal antibodies, antibody-drug conjugates, and targeted agents can penetrate the blood-brain barrier and reach metastatic sites in the central nervous system (CNS). Their brain-specific activity has led to improved quality of life and longer overall survival for patients who develop brain metastasis along with breast cancer, said Dr. Pegram, who is also Medical Director of the Clinical and Translational Research Unit and Associate Dean for Clinical Research Quality at Stanford.
Mark Pegram, MD
“As systemic control improves for treating metastatic disease, particularly for HER2-positive breast cancer, the brain is increasingly becoming a sanctuary site. Many patients develop brain metastases when they are actually responding in the extracranial space to anticancer treatments,” Dr. Pegram said. “It’s remarkable how most of our chemotherapeutic drugs have poor penetration of the CNS. By contrast, antitumor antibodies can (and do) penetrate the blood-brain barrier and can access tumor targets on cancer cells in the brain.”
A recent systematic review confirmed the following risk factors for breast cancer–related brain metastases: HER2 amplification or overexpression, triple-negative subtype, high histologic grade, increased Ki67 expression, nodal involvement, multiple metastatic sites, short time to distant relapse, tumor size > 2 cm, and young age.2 Hormone receptor negativity has also been associated with brain metastases. Once brain metastases are diagnosed, expected median overall survival has historically been worrying—about 1 year. In one study, brain metastases were noted as the cause of death in about 70% of these patients with CNS involvement.3
Zirconium (Zr-89)-labeled trastuzumab positron-emission tomography has been shown, on imaging, to gain access to the CNS. “This gave us the idea to try using antibodies in higher doses to increase concentrations in the brain metastasis microenvironment,” said Dr. Pegram. In one study of 37 patients who received high-dose intravenous trastuzumab (6 mg/kg weekly) with standard–dose and schedule pertuzumab (after prior radiation therapy), durable responses were observed.4
“I thought this was fairly intriguing,” said Dr. Pegram, who was a co-investigator of the study. “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 other antibody-based therapeutics as well, such as antibody-drug conjugates.”
HER2-targeted antibody-drug conjugates are indeed showing promise as brain-targeting agents, though data remain somewhat limited due to sample size constraints. In an Italian study of 53 patients, ado-trastuzumab emtansine (T-DM1) achieved an intracranial response rate of 30.1%, not much lower than the 35.1% extracranial response rate and the 38.3% response rate in patients without brain metastases.5
Dr. Pegram commented: “This was quite gratifying…. It was a small study but pretty remarkable data…establishing proof of concept that antibody-drug conjugates may have particular activity in the brain.”
More recently, the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) set a new benchmark for clinical activity in metastatic HER2-positive breast cancer based on a more than doubling in 12-month progression-free survival vs T-DM1 in DESTINYBreast03.6 In patients with brain metastases, T-DXd achieved an intracranial objective response rate of 63.9% vs 33.4% with T-DM1, with more than one-fourth of patients treated with T-DXd having complete responses in the brain.7
“Unique activity” in the brain has also been shown for the small-molecule inhibitor tucatinib given with trastuzumab and capecitabine. In the HER2CLIMB clinical trial, treatment with the triplet led to an intracranial response rate of 47.3%, vs 20.0% with trastuzumab/capecitabine.8 In patients with brain metastases, the addition of tucatinib was associated with a 9-month improvement in median overall survival and almost a 50% decrease in the development of new brain lesions.
In addition, progression-free survival in the CNS more than doubled in patients with active brain metastases (hazard ratio [HR] = 0.339; P < .0001) and stable lesions (HR = 0.406; P = .01). For the group with active lesions, a significant overall survival benefit was also observed (HR = 0.524; P = .00087), whereas a nonsignificant numerical increase in overall survival was seen in the group with stable lesions. As Dr. Pegram noted, patients with active lesions are “the most challenging to treat,” as they often have troubling symptoms that can reflect disease that is progressing. He noted that tucatinib was given without diminishing quality of life, vs the doublet as well. “That’s what treatment of brain metastases is all about—maintaining quality of life and improving overall survival,” he said.
With approximately half of patients demonstrating brain lesions at study entry, HER2CLIMB was a “a fantastic opportunity to look at the efficacy signals uniquely in that population with HER2-positive metastatic disease, in a phase III randomized trial,” he added.
Furthermore, activity in leptomeningeal metastasis has now been suggested for tucatinib/trastuzumab/capecitabine. In the phase II nonrandomized TBCRC049 trial, which involved patients with newly diagnosed leptomeningeal disease, the triplet was associated with a median overall survival of about 10 months vs just 4 to 5 months based on historical controls. Though the numbers in the study so far are small, this result represents the first prospective evidence of clinical benefit with systemic therapy in this subset of patients with HER2-positive leptomeningeal disease.9
“Tucatinib-based therapy improves overall survival for patients with HER2-positive breast cancer brain metastases while maintaining overall health-related quality of life and may include some potential benefit in leptomeningeal disease,” he commented.
Screening and Treatment
The agents discussed here have earned a role in the treatment of brain metastases in patients with HER2-positive breast cancer, according to Dr. Pegram. He described how he employs them in the clinic.
Following a taxane and dual-antibody therapy (trastuzumab and pertuzumab) in the first line, T-DXd is now the preferred regimen for patients without brain metastases. For those with active CNS disease, “clearly, the tucatinib/trastuzumab/capecitabine regimen is a strong consideration because of level 1 evidence of an overall survival benefit from a randomized phase III trial,” Dr. Pegram explained. “For patients with stable brain metastases, it’s probably more of a toss-up, and T-DXd or tucatinib-based therapy could be discussed with such patients. Indeed, at the end of the day many patients will receive both therapeutic approaches and so the order in which we give them may not matter much in the grand scheme of things.”
Guidelines that recommend screening for CNS metastases only for symptomatic patients may not adequately capture all patients with brain metastases.— Mark Pegram, MD
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Clinical guideline committees might also need to revise their recommendations regarding identifying patients who may benefit from these drugs, suggested Dr. Pegram. Current guidelines generally recommend screening only those HER2-positive patients whose symptoms point to the presence of CNS involvement.
“Guidelines that recommend screening for CNS metastases only for symptomatic patients may not adequately capture all patients with brain metastases. If your treatment decision will be affected by whether or not patients have brain metastases, MRI could be indicated even in selected asymptomatic patients,” he said. That said, Dr. Pegram does not recommend routine screening brain MRIs for all metastatic patients at all restaging intervals. Rather, MRIs should rightly be reserved for symptomatic patients suspected of harboring brain metastasis and those patients for whom a particular treatment decision could be influenced by knowledge of the presence of brain metastases.
DISCLOSURE: Dr. Pegram disclosed relationships with Seagen, AstraZeneca, Daiichi Sankyo, and Roche/Genentech.
2. Koniali L, Hadjisavvas A, Constantinidou A, et al: Risk factors for breast cancer brain metastases: A systematic review. Oncotarget 11:650-669, 2020.
3. Mounsey LA, Deal AM, Keith KC, et al: Changing natural history of HER2-positive breast cancer metastatic to the brain in the era of new targeted therapies. Clin Breast Cancer 18:29-37, 2018.
4. Lin NU, Pegram M, Sahebjam S, et al: Pertuzumab plus high-dose trastuzumab in patients with progressive brain metastases and HER2-positive metastatic breast cancer: Primary analysis of a phase II study. J Clin Oncol 39:2667-2675, 2021.
5. Fabi A, Alesini D, Valle E, et al: T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer. Breast 41:137-143, 2018.
6. Cortés J, Kim S, Chung W, et al: Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: Results of the randomized phase III DESTINY-Breast03 study. ESMO Congress 2021. Abstract LBA1. Presented September 18, 2021.
7. Hurvitz S, Kim SB, Chung WP, et al: Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: Subgroup analysis from the randomized phase 3 study DESTINY-Breast03. 2021 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 9, 2021.
8. Lin NU, Borges V, Anders C, et al: Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol 38:2610-2619, 2020.
9. Murthy RK, O’Brien B, Berry DA, et al: Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis in HER2-positive breast cancer: Results from TBCRC049, a phase 2 non-randomized study. 2021 San Antonio Breast Cancer Symposium. Abstract PD4-02. Presented December 8, 2021.