Journal: Nature cancer
Phase 2, single‑arm, multicenter study of tucatinib–trastuzumab–capecitabine in HER2‑positive breast cancer with newly diagnosed leptomeningeal metastases.
Design and population
- • Nonrandomized phase 2 trial; primary endpoint: overall survival.
- • 17 women with MRI‑confirmed leptomeningeal metastases; 88% symptomatic, 47% with positive CSF cytology at baseline.
- • Systemic regimen: tucatinib combined with trastuzumab and capecitabine.
- • Median follow‑up: 18 months (range 9.0–26.7); 41% (6/17) alive at data cutoff.
Efficacy
- • Met prespecified interim efficacy threshold and surpassed historical median OS of 4.4 months used as control.
- • Median overall survival: 10 months (95% CI 4.1 months, not reached).
- • Median time to CNS progression: 6.9 months (95% CI 2.8–13.8 months).
- • LM objective response (composite endpoint) in 5/13 evaluable patients (38%).
- • Neurological improvement in 7/12 evaluable patients (58%).
Pharmacokinetics
- • Tucatinib achieved therapeutic concentrations in cerebrospinal fluid, supporting CNS and leptomeningeal penetration.
Safety
- • Safety was systematically evaluated; no specific toxicity signals are detailed in the abstract beyond overall feasibility of the regimen.
Clinical implications
- • In a setting with historically dismal outcomes and limited options, this prospective study shows that a fully systemic HER2‑targeted regimen can produce:
- • Prolonged survival compared with historical benchmarks,
- • Objective leptomeningeal responses,
- • Clinically meaningful neurological improvement.
- • Supports the role of systemic HER2‑directed therapy as a treatment approach for leptomeningeal metastases from HER2‑positive breast cancer.