Tucatinib–trastuzumab–capecitabine for treatment of leptomeningeal metastasis in women with HER2+ breast cancer: TBCRC049 phase 2 study results

作者：Rashmi K. Murthy, Barbara J. O’Brien, DA Berry, Akshara Singareeka-Raghavendra, Maria Gule Monroe, Jason Johnson, Jason White, Jill Schwartz-Gomez, A. Topletz-Erickson, Mina Lobbous, K. Riley, Michelle Melisko, Aki Morikawa, Sherise D. Ferguson, John F. de Groot, Ian E. Krop, Vicente Valero, Mothaffar F. Rimawi, Antonio C. Wolff, Debu Tripathy, Nancy U. Lin, Erica Stringer-Reasor · 发表于：Nature Cancer · 年份：2026 · DOI：10.1038/s43018-026-01120-7 · 被引用次数：1 · 研究领域：Brain Metastases and Treatment、Lung Cancer Research Studies、Cancer Treatment and Pharmacology

Treatments for leptomeningeal metastasis (LM) are limited and prognosis is poor. In this phase 2, nonrandomized, single-arm, multicenter study, we evaluated a tucatinib–trastuzumab–capecitabine regimen in patients with newly diagnosed LM and human epidermal growth factor receptor 2-positive (HER2+) breast cancer. The primary endpoint was overall survival; secondary endpoints included central nervous system progression-free survival, LM objective response, neurological symptom improvement, pharmacokinetics and safety. The trial met its prespecified interim efficacy threshold and exceeded the historical control of 4.4 months. Among 17 enrolled women, all had magnetic resonance imaging-confirmed LM, 15 (88%) were symptomatic and 8 (47%) had abnormal cerebrospinal fluid cytology. For a median follow-up of 18 months (range 9.0–26.7 months), 6 of 17 (41%) remained alive. Tucatinib reached therapeutic levels in the cerebrospinal fluid. The median overall survival was 10 months (95% confidence interval 4.1 months, not reached). The median time to central nervous system progression was 6.9 months (95% confidence interval 2.8, 13.8 months). Of 13 response-evaluable patients, 5 (38%) achieved composite LM objective response. Of 12 evaluable patients, 7 (58%) had improved neurological deficits. This prospective study suggests clinical benefit with a systemic regimen for HER2+ LM including objective responses, improved symptoms and extended survival. These data support systemic therapy as...