Abstract Background: Treatment options for HER2+ leptomeningeal disease (LMD) remain limited with a high unmet clinical need. The use of IT trastuzumab has been studied in the management of HER2+ breast LMD. We previously reported 80 mg as the recommended phase II dose of IT pertuzumab alongside 80 mg IT trastuzumab and now report results from the pre-specified interim analysis. Methods: The study is a multi-institutional, phase II trial of radiation therapy followed by IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. HER2+ LMD patients identified by magnetic resonance imaging (MRI) and/or cerebrospinal fluid cytology with a life expectancy 8 weeks, and KPS ≥ 60 were eligible. There was no limit on prior IT or systemic therapies. The primary objective was to evaluate overall survival (OS) following study treatment. Clinical trial information: NCT04588545. Results: A total of 20 patients were enrolled to the phase II study between November 2022 and February 2025. Median age was 48 (range: 33-63) and 8 patients (40%) had a baseline KPS ≤ 70. Eleven patients (55%) were hormone receptor (HR)-/HER2+ and 9 (45%) were HR+/HER2+. Median follow-up is 20.7 months. Median survival has not been reached (95% CI: 19.4 - Not reached (NR)) with a 12-month OS of 86%. Median LMD progression free survival (LMD-PFS) has not been reached (95% CI: 7.2 - NR) with a 12-month LMD-PFS of 65%. The best LMD response has been a complete response in 4 (20%), partial response in 5 (25%), and stable disease in 11 (55%) of patients. The most common grade ≥ 2 adverse events attributed to IT trastuzumab/pertuzumab included fatigue (n=3; 15%), headache (n=2; 10%), and nausea/vomiting (n=2; 10%). Currently, twelve patients (60%) continue study therapy with 28.1 months as the longest treatment duration. Conclusions: The study met its predetermined endpoint for OS to warrant continuing enrollment in the second stage of the phase II trial. Initial trial results are encouraging with study therapy that is well tolerated. Citation Format: K. Ahmed, P. Kumthekar, Y. Pina, Y. Kim, M. DeJesus, G. Rico, S. Mannarino, B. Evernden, L. Sharp, D. Primdahl, R. Lukas, D. Oliver, P. Grogan, A. Armaghani, R. Costa, A. Soyano, J. Arrington, H. Soliman, H. Yu, H. Han, P. Forsyth. Radiation Therapy Followed by Intrathecal (IT) Trastuzumab/Pertuzumab in the Management of HER2+ Breast Leptomeningeal Disease: Interim Results from a Phase II Multi-Institutional Study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD13-08.
Ahmed et al. (Tue,) studied this question.