Researchers at MD Anderson Cancer Center have reported that a combination therapy of tucatinib, trastuzumab, and the chemotherapy drug capecitabine improved the survival of some breast cancer patients with leptomeningeal metastasis (LM). The Phase II study of 17 patients with LM and HER2-positive breast cancer, published in Nature Cancer, showed the combination therapy increased survival to 10 months, up from the historical average of 4.4 months, and at 18 months post treatment 41% of the patients were still alive.
“The combination achieved a clinically meaningful improvement in overall survival compared to historical controls,” said Rashmi Murthy. “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.”
LM occurs when cancer cells spread to the leptomeninges and cerebrospinal fluid surrounding the brain and spinal cord. “LM refers to the seeding of tumor cells to the leptomeninges and/or cerebrospinal fluid (CSF),” the researchers wrote. “Classically, LM presents with multifocal neurological deficits and progressive neurological decline and is diagnosed based on clinical findings, neuroaxis imaging findings and/or CSF cytology.” Treatment of this metastatic disease is difficult because many drugs cannot effectively cross the blood-brain barrier into the cerebrospinal fluid, and because LM is not a solid tumor but is dispersed cancer cells within spinal fluid, making targeted delivery challenging.
The MD Anderson team selected the combination of tucatinib, trastuzumab, and capecitabine based on prior evidence in metastatic HER2-positive breast cancer, particularly in patients with brain metastases. Tucatinib is a small-molecule HER2-targeted tyrosine kinase inhibitor (TKI) designed to penetrate the central nervous system more effectively than antibody-based therapies. Trastuzumab targets the HER2 receptor on cancer cells, while capecitabine is an oral chemotherapy. Earlier studies, including the HER2CLIMB trial, demonstrated improved progression-free and overall survival with this regimen in patients with brain metastases, but didn’t include patients with LM. “Importantly, HER2CLIMB demonstrated a clinically meaningful and statistically significant improvement in (progression free survival) and a clinically important improvement in OS among patients with brain metastases…however… patients with LM were excluded… leaving unknown the efficacy of this regimen in this important subgroup,” the researchers wrote.
The Phase II, nonrandomized, single-arm, multicenter trial enrolled women with newly diagnosed LM and HER2-positive breast cancer. All patients had MRI-confirmed disease, most were symptomatic, and nearly half had abnormal cerebrospinal fluid cytology. Patients received 21-day cycles of oral tucatinib and capecitabine along with intravenous trastuzumab.
Median overall survival reached 10 months, more than double the historical average of 4.4 months. At a median follow-up of 18 months, 41% of patients remained alive. The median time to central nervous system progression was approximately seven months. In addition to survival outcomes, the treatment demonstrated clinical activity within the central nervous system. “Of 13 response-evaluable patients, five (38%) achieved composite LM objective response. Of 12 evaluable patients, seven (58%) had improved neurological deficits,” the researchers wrote.
Pharmacokinetic analysis provided insight into how the regimen may be working in LM. Tucatinib and its metabolite were detected in the cerebrospinal fluid at levels comparable to plasma concentrations, which aided its ability to cross the blood-brain barrier into the central nervous system.
The findings suggest that systemic therapy could play a larger role in managing LM, potentially reducing reliance on more invasive treatments such as intrathecal chemotherapy or radiation. The researchers said the combination therapy could allow clinicians to treat both LM and other sites of metastasis simultaneously, while also offering the possibility of delaying treatments that can negatively affect quality of life.
The study also raises questions about how best to sequence therapies for patients with HER2-positive LM. Future research will explore combinations with intrathecal treatments and will look for biomarkers that can predict which patients are most likely to benefit from this treatment method. This will include evaluation of circulating tumor DNA in blood and cerebrospinal fluid to better understand mechanisms of response and resistance.
