A Phase II study conducted by researchers at The University of Texas MD Anderson Cancer Center has identified a combination of targeted therapies—tucatinib and trastuzumab—along with the chemotherapy drug capecitabine, that may improve symptoms and extend survival in some HER2+ breast cancer patients with leptomeningeal metastasis (LM).
Historically, patients with LM have had limited treatment options, but new findings suggest a significant step forward.
Study Findings
The study, published in Nature Cancer, included 17 female patients with newly diagnosed LM and HER2+ breast cancer.
- Overall Survival: Median overall survival for patients treated with the combination therapy increased to 10 months, up from a historical average of 4.4 months. At the 18-month mark, 41% of participants were still alive.
- Disease Progression: The treatment also delayed disease progression, with a median of seven months before central nervous system progression.
- Neurologic Symptoms: Seven of 12 evaluable patients experienced improvements in neurologic deficits.
Dr. Rashmi Murthy, lead author, stated that for these patients, who often face limited treatment options, the results represent a step forward in how LM is treated and managed.
LM is challenging to treat due to the blood-brain barrier, which can block drugs from reaching metastatic cells in the spinal fluid, and the fluid-based nature of the metastatic cells themselves. Historically, research on this specific disease has been limited.
Dr. Barbara O'Brien, co-lead author, noted that observed improvements in neurologic symptoms were significant, as previous treatments for breast cancer LM primarily focused on disease stabilization rather than symptom improvement.
Treatment Mechanism
The combination therapy utilizes three agents to target cancer cells:
- Tucatinib: An oral targeted therapy that blocks the HER2 protein, which can promote breast cancer growth.
- Trastuzumab: A targeted antibody that binds to the HER2 protein on cancer cells, facilitating their destruction by the immune system.
- Capecitabine: An oral chemotherapy drug that converts into 5-fluorouracil (5-FU) in the body, targeting rapidly dividing cancer cells.
Study Details and Limitations
The single-arm, non-randomized, multi-phase study enrolled patients across four U.S. sites, including UT MD Anderson. Eligible patients were at least 18 years old with histologically confirmed metastatic HER2+ breast carcinoma. Participants received 21-day cycles of:
- Oral tucatinib (300 mg twice daily)
- Oral capecitabine (1000 mg/m2 twice daily on days 1-14)
- Intravenous trastuzumab (6 mg/kg) on day 21
Reported side effects included diarrhea, nausea, vomiting, hand-foot syndrome, and elevated liver function tests. Most adverse effects improved or resolved with appropriate care and dose modifications. One patient discontinued the combination due to alanine aminotransferase elevation, with symptoms resolving within one month.
Despite promising results, the study faced challenges and has inherent limitations.
Study limitations included early termination due to slow patient accrual, which occurred after the FDA approved a similar combination therapy. Additionally, the rarity of LM from HER2+ metastatic breast cancer meant the study design relied on a limited amount of available retrospective evidence.