Abstract P3-08-22: Tucatinib, Trastuzumab and Capecitabine with brain and/or spinal radiotherapy (XRT) in patients with HER2+ metastatic breast cancer and leptomeningeal disease: A multi-centre phase II, single arm feasibility study ("CLIMB LMD"; NCT

Abstract Background: As patients with HER2+ metastatic breast cancer (MBC) live longer and survive to experience spread of cancer to the brain, the incidence of leptomeningeal disease (LMD) is increasing. Unfortunately, patients with HER2+ LMD have a very poor prognosis with limited treatment options. Patients with LMD were excluded from the pivotal HER2CLIMB trial, which demonstrated intra-cranial activity of tucatinib, trastuzumab and capecitabine and prolonged survival among patients with HER2+ MBC. Methods: A multi-center phase II, single arm feasibility study with a safety run-in of 6 patients. The sample size will include 30 patients in total across participating centres in Ontario, Canada. Intervention: In phase 1, brain and/or spinal radiotherapy (XRT) will be administered. Areas in the brain and spine will be treated as per the discretion of the treating radiation oncologist. In phase 2, patients will commence systemic therapy between 7 days and up to 21 days after completion of brain and/or spinal XRT. Tucatinib, trastuzumab (Ogivri; MYL-1401O) and capecitabine will be administered as per the HER2CLIMB protocol; however, the addition of capecitabine may be delayed and commence during Cycle 2, at the discretion of the treating physician to allow for adequate recovery from XRT. Treatment will continue until disease progression or unacceptable toxicity. Patients who receive XRT but do not pass through the second phase of eligibility will not be counted towards the total patient number and will be followed for survival only. If >70% of enrolled patients experience one or more grade 3+ attributable AEs or SAEs, or >25% experience one or more grade 4+ attributable AEs or SAEs, these instances will be reported to the Data and Safety Monitoring Board (DSMB) in a timely fashion and will trigger review by the DSMB. The trial will continue until the DSMB reviews AE reports and decides whether or not the trial needs to be halted or terminated. Key inclusion criteria: 1. Men or women with HER2+ MBC. HER2+ status will be defined in accordance with ASCO-CAP 2018 guidelines, and can be diagnosed at any time prior to enrolment; 2. Evidence of LMD* in the brain and/or spine (either positive cerebral spinal fluid cytology and/or magnetic resonance imaging evidence of LMD). Measurable disease in the central nervous system is not required. *The diagnosis of LMD can occur at any time prior to enrolment; 3. Age 18+ at time of consent; 4. ECOG ≤ 2. Key exclusion criteria: 1. Prior whole brain radiotherapy (prior stereotactic radiosurgery for parenchymal brain metastases received ≥7 days prior to consent is permitted); 2. Prior therapy specifically directed at LMD, including prior radiotherapy or systemic therapy; 3. Prior use of tucatinib at any time prior to enrollment. Primary outcome: Overall survival (OS) from the start of XRT. Secondary outcomes: i) Time to central nervous system (CNS) progression from the start of XRT; ii) Safety and tolerability (CTCAE v.5.0); iii) Progression free survival from the start of XRT; iv) CNS specific objective response (RANO-BM); v) Extracranial objective response (RECIST v1.1); vi) Neurologic-specific quality of life (QoL) (FACT-BR v.4); vii) Overall QoL (EORTC QLQ-C30 v.3). Analyses: OS will be measured from start of XRT until the date of death (from any cause, assessed up to 3 years), or censored at the last known follow-up. Kaplan-Meier curves will be used to present the time to event data. In addition to the median and 95% confidence interval, estimates of OS at different time points from the Kaplan-Meier survival curve will be tabulated. Accrual: This study opened for enrollment at the Sunnybrook Odette Cancer Centre in December 2023 and will open at the Ottawa Hospital Cancer Centre in July 2024. To-date (July 3, 2024), 4 patients have enrolled. The expected accrual period is 18 to 24 months. Citation Format: Katarzyna J. Jerzak, Marie-France Savard, Mary-Jane Lim-Fat, Gregory Pond, Hany Soliman, Arjun Sahgal. Tucatinib, Trastuzumab and Capecitabine with brain and/or spinal radiotherapy (XRT) in patients with HER2+ metastatic breast cancer and leptomeningeal disease: A multi-centre phase II, single arm feasibility study ("CLIMB LMD"; NCT06016387) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-22.