Patients with leptomeningeal metastasis have historically had few treatment options. Now, researchers have found a combination of the tyrosine kinase inhibitor tucatinib and the monoclonal antibody trastuzumab, plus the chemotherapy capecitabine, may improve symptoms and extend survival in some patients with breast cancer and leptomeningeal metastasis.
The phase II TBCRC049 study, results of which were published by Murthy et al in Nature Cancer, included 17 female patients with newly diagnosed leptomeningeal metastasis and HER2-positive breast cancer. Median overall survival 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. With the combination treatment, disease progression also stalled, with a median of 7 months before central nervous system progression. Seven 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, MD, Associate Professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center. “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.”
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, leptomeningeal metastasis 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 condition.
“In addition to encouraging survival outcomes, throughout this study we observed improvements in neurologic symptoms,” said co-lead author Barbara O’Brien, MD, Associate Professor of Neuro-Oncology at MD Anderson. “Treatments for breast cancer leptomeningeal metastasis have historically focused on stabilizing disease rather than improving symptoms, making these findings particularly meaningful and encouraging.”
More Study Results
Tucatinib is a targeted therapy 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 that turns into fluorouracil in the body to eliminate fast-growing cancer cells.
The single-arm, nonrandomized, multiphase study enrolled patients at four sites. Eligible patients were at least 18 years old with histologically proven metastatic HER2-positive 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 to 14 and intravenous trastuzumab (6 mg/kg) on day 21.
Side effects of the triplet 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 1 month.
Study limitations include early termination due to slow accrual following U.S. Food and Drug Administration approval of the combination therapy. Additionally, leptomeningeal metastasis from HER2-positive 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.
The authors concluded, “This prospective study suggests clinical benefit with a systemic regimen for HER2-positive leptomeningeal metastasis including objective responses, improved symptoms, and extended survival.”
DISCLOSURE: This study was sponsored by Translational Breast Cancer Research Consortium and its foundation partners: the Breast Cancer Research Foundation and Susan G. Komen and Seagen Inc. For full disclosures of the study authors, visit nature.com.
