Patients with leptomeningeal metastasis (LM) have historically had few
treatment options. Now, researchers from The University of Texas MD Anderson
Cancer Center have found a combination of targeted therapies, tucatinib and
trastuzumab, plus the chemotherapy drug, capecitabine, may improve symptoms and
extend survival in some breast cancer patients with LM.
The Phase II study, published today in Nature
Cancer, included 17 female patients with newly diagnosed LM and HER2+
breast cancer. Median overall survival (OS) in those treated with the
combination therapy increased from a historical average of 4.4 months to 10
months. At the 18-month mark, 41% of patients were still alive. Under the
combination treatment, disease progression also stalled, with a median of seven
months before central nervous system progression, and 7 of 12 evaluable
patients also had improved neurologic deficits.
"The combination achieved a clinically meaningful improvement in
overall survival compared to historical controls," said lead author Rashmi
Murthy, M.D., associate professor of Breast Medical Oncology. "For these
patients, who often face limited treatment options, our results represent a
step forward, offering new hope in how we treat and manage leptomeningeal
metastasis."
Limited treatments for patients with leptomeningeal
metastasis
Leptomeningeal metastasis is difficult to treat primarily because the
blood-brain barrier may block drugs from reaching the spinal fluid, where the
metastatic cells are found. Additionally, LM is not a solid tumor but is made
up of metastatic cells living in fluid, making them more difficult to target.
Historically, there also are few studies about this specific disease.
"In addition to encouraging survival outcomes, throughout this study we observed
improvements in neurologic symptoms," said co-lead author Barbara O'Brien,
M.D., associate professor of Neuro-Oncology. "Treatments for breast cancer
leptomeningeal metastasis have historically focused on stabilizing disease
rather than improving symptoms, making these findings particularly meaningful
and encouraging."
How the combination therapy works
Tucatinib is a targeted therapy pill
that blocks the HER2 protein, which helps some breast cancers grow. Trastuzumab
is a targeted antibody that attaches to the HER2 protein on cancer cells and
helps the immune system destroy them. Finally, capecitabine is a chemotherapy
pill that turns into 5-fluorouracil (5-FU) in the body to eliminate
fast-growing cancer cells.
The single-arm, nonrandomized, multiphase study enrolled patients at four
sites in the U.S., including UT MD Anderson. Eligible patients were at least 18
years old with histologically proven metastatic HER2+ breast carcinoma. These
patients were treated with 21-day cycles of oral tucatinib (300 mg)
twice daily, plus oral capecitabine (1,000 mg/m2) twice daily on days 1–14 and
intravenous trastuzumab (6 mg/kg) on day 21.
Other key findings
Side effects included diarrhea, nausea, vomiting, hand-foot syndrome, and
liver function test elevation. Most adverse effects improved or resolved with
appropriate care and dose modifications. One patient saw alanine
aminotransferase elevation after one cycle, which led to discontinuation of the
combination, and symptoms resolved after one month.
Study limitations include early termination due to slow accrual following Food & Drug Administration (FDA) approval of the combination therapy. Additionally, LM from HER2+ metastatic breast cancer is rare, resulting in limited published data. As a result, the study design was informed by the small amount of available retrospective evidence.
Source: Combination treatment benefits patients with advanced breast cancer that has spread to the brain
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