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Associate Professor of Medicine
Division of Breast Oncology
Harvard Medical School
Chief, Division of Breast Oncology
Breast Oncology Program
Dana-Farber Cancer Institute
Sara Tolaney, MD, MPH: research (paid to institution): AstraZeneca, Bristol-Myers Squibb, Cyclacel, Eisai, Exelixis, Genentech/Roche, Immunomedics/Gilead, Lilly, Merck, Nanostring, Nektar, Novartis, Odonate, Pfizer, Sanofi, Seattle Genetics; consulant: 4D Pharma, ARC Therapeutics, AstraZeneca, Athenex, BeyondSpring Pharmaceuticals, Blueprint Medicines, Bristol-Myers Squibb, Certara, Chugai, CytomX, Daiichi Sankyo, Eisai, Ellipses Pharma, Genentech, Immunomedics/Gilead, Kyowa Kirin Pharmaceuticals, Lilly, Mersana, Novartis, OncoPep, OncoSec, OncXerna, Pfizer, Puma, Reveal Genomics, Samsung Bioepsis, Sanofi, Seattle Genetics, Zentalis, Zetagen, Zymeworks.
Among patients with metastatic, HER2-positive breast cancer, approximately 50% will develop brain metastases. Managing brain metastases is a critical part of caring for this population. Traditionally, radiotherapy has been used for patients with a new brain metastasis, in the hope that local therapy will be sufficient to treat the metastasis in a patient whose disease is otherwise controlled with continued systemic therapy. Before the last few years, there were no agents that were proven to be able to treat central nervous system (CNS) metastases and result in an improved outcome in this population. Most of the pivotal registration trials of systemic therapies for patients with HER2-positive metastatic breast cancer (MBC) excluded patients with untreated or progressive brain metastases. If patients with brain metastases were included, they had to have “stable, treated” brain metastases, and so, most of the data that we had available for systemic agents were for these patients with no brain metastases or stable, treated brain metastases.
Current Data on Use of Systemic Therapy to Manage Brain Mets in HER2-Positive MBC
The randomized, phase II HER2CLIMB trial evaluated the addition of tucatinib to capecitabine and trastuzumab in HER2-positive breast cancer and had a very unique trial design. This study allowed patients with stable, treated brain metastases as well as patients with active, progressive brain metastases. The final overall survival (OS) analysis, published in the Annals of Oncology in 2022, confirmed statistically significant improvements in progression-free survival (PFS) (HR: 0.57) and OS (HR: 0.73) with tucatinib plus capecitabine and trastuzumab in the overall population. In the subset of patients with brain metastases, published in JAMA Oncology in 2022, there was a similar improvement in OS (HR: 0.60), with a median OS of 21.6 months with tucatinib plus capecitabine and trastuzumab vs 12.5 months with capecitabine and trastuzumab. In the subset of patients with active brain metastases, the median OS was 21.4 months with tucatinib plus capecitabine and trastuzumab vs 11.8 months with capecitabine and trastuzumab. This subgroup analysis also found that the addition of tucatinib reduced the risk of developing new brain lesions in the intention-to-treat study population (HR: 0.55).
These data changed our thinking with regard to brain metastases because it allows us to consider using systemic treatment instead of local therapy in select patients with breast cancer brain metastases. For example, a patient with multiple new brain metastases who is not a candidate for stereotactic radiotherapy could consider either whole-brain radiotherapy or hold off on the radiation and instead use systemic therapy with tucatinib plus capecitabine and trastuzumab to control the brain metastases.
One open question is, if whole brain radiation is not used and tucatinib plus capecitabine and trastuzumab successfully shrinks the tumors, when should radiation be integrated in the future? This depends on individual patient factors. If patients appear to have a CNS response, they may not need radiation and can continue with observation. If they develop CNS progression, radiation could be considered at this time. If patients have systemic progression, it is optimal to switch their therapy to another regimen with an agent that can penetrate the CNS.
Looking to the Future: Ongoing Studies for Patients With HER2-Positive MBC and Brain Mets
Neratinib, a pan-HER2 inhibitor, is another agent with activity in the CNS. In the phase III NALA study, the addition of neratinib to capecitabine and lapatinib in patients with breast cancer and at least 2 prior HER2-directed regimens significantly improved PFS and time to intervention for CNS disease compared with capecitabine and lapatinib alone. Despite meaningful activity, however, the combination of neratinib plus capecitabine is associated with substantial gastrointestinal toxicity, even when prophylactic loperamide is used. However, new results from an interesting phase II study (TBCRC 022) were presented at the 2022 San Antonio Breast Cancer Symposium, showing synergistic intracranial activity from combining neratinib and trastuzumab emtansine (T-DM1) in patients with either previously untreated or active HER2-positive brain metastases, with or without prior T-DM1.
It is now understood that even relatively large molecules such as T-DM1 and trastuzumab deruxtecan (T-DXd) can penetrate the CNS and be active there, as reported in several phase II studies in advanced breast cancer (eg, DEBBRAH, TUXEDO-1). However, the DESTINY-Breast03 trial demonstrated significant OS improvement, with a 36% reduction in the risk of death, with T-DXd compared with T-DM1 in patients with previously treated HER2-positive MBC, including in patients with baseline stable, treated brain metastases. The ongoing phase IIIb/IV Destiny-BREAST12 study of T-DXd in advanced HER2-positive breast cancer is allowing patients with active brain metastases and will provide a larger set of data with regards to efficacy of T-DXd in this population. More studies are needed to validate efficacy in patients with active brain metastases, but nevertheless it is clear that T-DXd is an option for those with stable, treated brain metastases.
The results from HER2CLIMB also raised other important questions. Now that there is an agent proven to benefit patients with brain metastases, should screening for brain metastases be part of a breast cancer workup? Although brain magnetic resonance imaging is commonly used to image patients with CNS symptoms, it is not currently used for screening. That said, clinical trials are currently evaluating MRI for screening in patients with metastatic, HER2-positive breast cancer, with the hope that neurological symptoms can be delayed by earlier intervention for brain metastases.
There is also a question of whether brain metastases could even be prevented with agents such as tucatinib. The addition of tucatinib to T-DM1 is currently being studied in patients with high-risk, HER2-positive, early-stage breast cancer and residual disease after neoadjuvant, HER2-directed therapy in the phase III CompassHER2 RD trial, with the goal of reducing invasive disease-free survival and also the incidence of CNS events. The same combination is also being explored in the HER2CLIMB-02 study, and will help us understand the efficacy in patients with metastatic HER2+ disease. The ongoing HER2CLIMB-05 phase III study is looking at the addition of tucatinib to trastuzumab and pertuzumab as maintenance therapy in patients with metastatic, HER2-positive breast cancer. The study is primarily designed to assess PFS, but there could be a secondary benefit in the prevention of CNS metastases.
Online Interactive Treatment Decision Support Tool
Given the complexity of treating our patients with HER2‑positive breast cancer, my colleagues and I have developed an interactive treatment decision support tool for patients with HER2-positive, metastatic breast cancer. This tool has been assembled, evaluated, and designed by 5 experts who treat patients with breast cancer. You can go online to enter key patient and disease characteristics to see recommendations from all 5 experts for your individual set of characteristics.
Your Thoughts? How do you manage patients with HER2-positive breast cancer and brain metastases? Share your thoughts in the comment box below.