Abstract PS5-09-07: Etic-lm : a multicenter, single-arm, phase 2 study evaluating the efficacy of oral tucatinib, oral capecitabine, and intrathecal trastuzumab in patients with her2-positive metastatic breast cancer with leptomeningeal metastases, a ucbg study

Abstract Background: Leptomeningeal metastases (LM) are a rare but devastating form of disease progression in HER2-positive (HER2+) metastatic breast cancer (MBC), occurring in 5-10% of patients. Median overall survival (OS) historically ranges from 4 to 6 months, with poorer outcomes observed in type 1 LM (characterized by the presence of tumor cells in the cerebrospinal fluid (CSF)), and longer OS reported with newer therapies such as trastuzumab deruxtecan (T-DXd), brain-penetrant HER2 tyrosine kinase inhibitors, or intrathecal (IT) trastuzumab. Tucatinib is a highly selective HER2 tyrosine kinase inhibitor that has demonstrated significant intracranial activity in HER2+ MBC with brain metastases, including in heavily pretreated patients, when combined with intravenous trastuzumab and oral capecitabine. IT trastuzumab has shown encouraging signs of efficacy without safety concerns in two prospective studies in HER2+ MBC with LM, offering one of the few targeted strategies capable of delivering anti-HER2 therapy directly into the CSF, thereby bypassing the blood-CSF barrier. Based on the complementary pharmacological properties and mechanisms of action of these agents, the ETIC-LM trial was designed to evaluate the efficacy and safety of a triplet regimen composed of oral tucatinib, oral capecitabine and IT trastuzumab in patients with HER2+ MBC and LM, including those previously exposed to T-DXd and those presenting with the most severe form of LM: type 1 LM. Trial design: ETIC-LM is a national, open-label, single-arm phase II study enrolling patients with histologically confirmed HER2+ MBC and LM confirmed by MRI and/or presence of tumor cells in the CSF. Eligible patients must have an ECOG performance status of 0 to 2 and evaluable disease according to RANO-LM and RECIST1.1 criteria. The investigational treatment consists of oral tucatinib (300 mg twice daily, continuously), oral capecitabine (1000 mg/m2 twice daily on days 1 to 14 of each 21-day cycle), and intrathecal trastuzumab (150 mg weekly, administered via lumbar puncture or Ommaya reservoir). Treatment is continued until disease progression, unacceptable toxicity, or patient withdrawal. Objectives: The primary objective is to evaluate the 12-month overall survival (12m-OS) rate. Secondary objectives include the assessment of neurological symptom improvement using the NANO scale, progression-free survival (PFS), LM-specific and brain-specific PFS using RANO-LM, OS, CSF cytological response at 4 weeks, quality of life (assessed by EORTC QLQ-C30 and BN20 questionnaires), and cognitive function (evaluated using the Montreal Cognitive Assessment (MoCA)). Safety endpoints include the incidence and severity of adverse events according to CTCAE version 5.0, as well as longitudinal cognitive evaluations. Ancillary studies aim to explore pharmacokinetics and potential biomarkers in CSF and plasma. Statistical Methods: Using a Fleming single-stage design, the trial aims to detect an increase in 12-month overall survival (12m-OS) from 20% (null hypothesis) to 45% (alternative hypothesis), with 90% power and a one-sided alpha of 5%. A total of 29 evaluable patients are required. If at least 10 patients are alive at 12 months, the regimen will be considered worthy of further investigation. Current Status: The trial began enrollment in February 2024. As of June 2025, 11 patients have been enrolled. Recruitment is ongoing (NCT05800275). Funding: Pfizer Citation Format: L. Larrouquere, S. Chabaud, C. Poisson, G. Emile, C. Bailleux, A. Darlix, C. Jouannaud, S. Mijonnet, T. Roque, T. Bachelot. Etic-lm : a multicenter, single-arm, phase 2 study evaluating the efficacy of oral tucatinib, oral capecitabine, and intrathecal trastuzumab in patients with her2-positive metastatic breast cancer with leptomeningeal metastases, a ucbg 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 PS5-09-07.