By: Mike Basset
From: medpagetoday.com
About 110,000 new cases of leptomeningeal disease (metastases of cerebrospinal fluid or the thin membranes that surround the brain and spinal cord) are diagnosed each year in the U.S., with the incidence varying among cancer types.
Among breast cancer patients, incidence ranges between 5% and 8%
. Patients with HER2-positive status are at particularly high risk
of leptomeningeal metastases and face a poor prognosis when it develops, with median survival of 4-12 months after diagnosis despite multimodality therapy.
“We’ve seen the development of many new therapeutic strategies specifically for HER2-positive breast cancer that are doing an excellent job of being able to control systemic disease, but, of course, there’s still much work needed in the metastatic setting,” said Rashmi Murthy, MD, of the University of Texas MD Anderson Cancer Center in Houston. And leptomeningeal disease “is considered to be a rare entity, but we’re really seeing it more and more,” she added.
Symptoms are primarily neurological, the most common of which include headache, nausea, vomiting, weakness or numbness in the arms and legs, vision and hearing changes, and problems walking or balancing. Other symptoms can include mood or behavior changes, dizziness, cognitive issues, difficulty controlling bladder or bowel movements, and confusion or hallucinations.
These metastases can be difficult to diagnose, said Sara Hurvitz, MD, of the University of Washington and Fred Hutch Cancer Center in Seattle. “It usually doesn’t present as a mass, but rather can be imaging occult, requiring lumbar puncture and analysis of CSF [cerebrospinal fluid] to find the malignant cells,” she said.
Leptomeningeal disease (LMD) can also be challenging to follow, said Murthy. “I think one of the most important things — especially at academic centers, such as where I practice — is to work very collaboratively with our neuro-oncologists or neuroradiologists, and really that starts from the time that we suspect LMD.”
In terms of leptomeningeal disease treatment, “its distribution can be diffuse, so it is not amenable to surgical removal,” noted Hurvitz, “and use of radiation to the entire spinal cord and brain would be too toxic.”
Intrathecal chemotherapy reaching directly into the cerebrospinal fluid where the disease is has been a traditional method of treating leptomeningeal metastases, as has the use of radiation therapy, while there have also been studies evaluating the use of intrathecal trastuzumab.
More recently, studies have begun to look at targeted and systemic therapies like the tyrosine kinase inhibitor tucatinib (Tukysa) and antibody-drug conjugate trastuzumab deruxtecan (Enhertu, T-DXd).
Following on the success of the HER2CLIMB regimen
of tucatinib, trastuzumab, and capecitabine in heavily treated metastatic HER2-positive breast cancer (with or without brain metastases), Murthy’s group conducted a phase II study, published in Nature Cancer, showing the combination may improve symptoms and extend survival in some patients with leptomeningeal disease.
he study included 17 women with newly diagnosed leptomeningeal metastases and HER2-positive breast cancer. Median overall survival in those treated with the combination therapy increased to 10 months compared with what the authors calculated was a historical average of 4.4 months. At the 18-month mark, six of 17 patients (41%) were still alive.
The combination treatment also delayed disease progression, with a median of 6.9 months before central nervous system progression. In addition, objective responses occurred in five of 13 evaluable patients (38%), while seven of 12 evaluable patients (58%) had improved neurologic deficits.
“With median survival being measured in months, the survival that we saw, which was a median of approximately 10 months, was a substantial improvement,” Murthy said. “Of course, you know these numbers tell you that we still have a long way to go.”
, co-author Barbara O’Brien, MD, also of MD Anderson, noted that “throughout this study we observed improvements in neurologic symptoms. Treatments for breast cancer leptomeningeal metastasis have historically focused on stabilizing disease rather than improving symptoms, making these findings particularly meaningful and encouraging.”
The study “addresses a major unmet need … in a patient population that historically has not been included in many clinical trials,” Murthy added. “We hope that this study serves as a starting place for everyone involved in advancing cancer care to really be aware that these patients are able to participate in research. And, I think it demonstrates we can make advances, especially when we get the right teams together.”
In another small study
, all eight patients with heavily pretreated HER2-positive metastatic breast cancer and progressing leptomeningeal metastases who were treated with T-DXd derived clinical benefit. Four patients (50%) had an objective partial response based on formal neuroradiology MRI reads.
Murthy also noted that some investigational agents are being evaluated in this space as well, such as RO7771950 in the BREnnAtrial.
In that phase II/III study, RO7771950 is being tested against tucatinib, both in combination with trastuzumab and capecitabine, among patients with pretreated, unresectable locally advanced or metastatic HER2-positive breast cancer, including those with leptomeningeal metastases.
RO7771950 “is a more powerful HER2-specific tyrosine kinase inhibitor than tucatinib,” Murthy said. “We know that it has blood-brain penetrant properties, and patients with brain metastases have actually been included in the critical development of this drug. Now it’s being tested in this randomized trial that’s opening across many sites, and that protocol actually allows for patients with LMD.”
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.