Combination therapy shows promise for leptomeningeal metastasis in breast cancer

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 seven of 12 evaluable patients also had improved neurologic deficits. 

The combination achieved a clinically meaningful improvement in overall survival compared to historical controls. 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." 

Rashmi Murthy, M.D., lead author, associate professor of Breast Medical Oncology

Why are there 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 do the treatments in this combination therapy work? 

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, non-randomized, multi-phase 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 (1000 mg/m2) twice daily on days 1-14 and intravenous trastuzumab (6 mg/kg) on day 21. 

What are other key findings of the study? 

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.