Abstract PD4-02: Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis (LM) in HER2-positive breast cancer: Results from TBCRC049, a phase 2 non-randomized study
Authors: Murthy Rashmi K , O'Brien Barbara , Berry Donald A , Singareeka-Raghavendra Akshara , Monroe Maria Gule , Johnson Jason , White Jason , Childress Jennifer , Sanford Justin , Schwartz-Gomez Jill , Melisko Michelle , Morikawa Aki , Ferguson Sherise , de Groot John F , Krop Ian , Valero Vicente , Rimawi Mothaffar , Wolff Antonio , Tripathy Debu , Lin Nancy U , Stringer-Reasor Erica 
Published: March 2022

Background: Treatment options for patients (pts) with leptomeningeal metastasis (LM) are limited, and the prognosis is poor (median overall survival (OS) ~ 4-5 months). Tucatinib is a potent and highly selective HER2-targeted tyrosine kinase inhibitor approved for use in combination with trastuzumab and capecitabine in pts with metastatic HER2+ breast cancer who have received ≥1 prior HER2-based regimen in the metastatic setting, including pts with brain metastases. TBCRC049 (NCT03501979) is an investigator-initiated, phase 2, single-arm study evaluating the safety and efficacy of tucatinib, trastuzumab and capecitabine in HER2+ breast cancer with newly diagnosed LM. We have previously demonstrated therapeutic levels of tucatinib in CSF in pts with HER2+ LM (Stringer-Reasor et al, ASCO 2021). We now report efficacy outcomes of the study. Methods: Eligible pts were adults with HER2+ metastatic breast cancer, Karnofsky performance status (KPS) &gt; 50, and newly diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Pts with treated or concurrent/new brain metastases were allowed. Pts received tucatinib 300 mg orally twice daily starting with cycle 1, day 1 (C1D1); capecitabine 1000 mg/m2 orally twice daily on days 1-14 of a 21-day cycle, starting on C1D1; and trastuzumab loading dose of 8 mg/kg IV on C1D1, and then 6 mg/kg IV once every 21 days, starting with C2D1. The primary endpoint was OS. Planned enrollment was 30 pts; however, due to lack of accrual since the FDA approval of tucatinib (4/2020), the study was closed after 17 patients were enrolled. Results: Baseline disease characteristics at LM diagnosis are shown in Table 1. Eight pts (47%) had abnormal CSF cytology (positive or equivocal). All pts had MRI evidence of LM in the brain, and 14/17 (82%) had brain metastases, of which 11 (65%) had received prior treatment for brain metastases. Median age at study treatment initiation was 53 years. Median number of treatment cycles received was 5 (range: 2-27). Median OS time was 11.9 months (95% CI: 4.1, NR). At data cutoff (6/22/21), 7/17 pts (41%) remained alive and median followup was 17 months(8-26). Median time to CNS progression was 6.9 months (95% CI: 2.8, 13.8). Conclusions: In pts with LMD from HER2+ metastatic breast cancer who were treated with tucatinib, trastuzumab, and capecitabine, the median OS time was nearly 1 year. This is the first prospective evidence of clinical benefit with a systemic regimen for HER2+ LM. Further studies evaluating brain-penetrant oral drugs in this rare pt population are needed.

Baseline Disease Characteristics (N=17)Number%Baseline CSF cytologyPositive529%Negative847%Equivocal318%None obtained1*6%Symptoms attributable to LMDYes1588%No212%MRI evidence of LMDBrain only1165%Brain and Spine635%History of brain metastasisYes1482%Prior treatment1165%New/concurrent diagnosis – no prior treatment318%No318%Extra-CNS DiseaseYes1165%No635%*One patient had VP shunt and difficulty sampling fluid; all CSF sent for research PK and non-PK studies

Citation Format: Rashmi K Murthy, Barbara O'Brien, Donald A Berry, Akshara Singareeka-Raghavendra, Maria Gule Monroe, Jason Johnson, Jason White, Jennifer Childress, Justin Sanford, Jill Schwartz-Gomez, Michelle Melisko, Aki Morikawa, Sherise Ferguson, John F de Groot, Ian Krop, Vicente Valero, Mothaffar Rimawi, Antonio Wolff, Debu Tripathy, Nancy U Lin, Erica Stringer-Reasor. Safety and efficacy of a tucatinib-trastuzumab-capecitabine regimen for treatment of leptomeningeal metastasis (LM) in HER2-positive breast cancer: Results from TBCRC049, a phase 2 non-randomized study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-02.