CTNI-71. INTERIM ANALYSIS OF A PHASE IIA TRIAL OF LAT1-TARGETED QBS72S IN BREAST CANCER LEPTOMENINGEAL DISEASE

Abstract Leptomeningeal disease (LMD) represents a severe complication of advanced cancer, with a significant symptom burden, poor prognosis, and limited treatment options. A central challenge in development of systemic therapies for LMD is the inability of such medications to cross the blood-brain barrier (BBB). We evaluated the safety and efficacy of QBS72S, a novel chemotherapeutic which leverages the L-type amino acid transporter 1 (LAT1) to permeate the BBB, in a single-arm, open-label phase IIa trial for LMD from breast cancer. Ten female patients with breast cancer LMD were included, with a median age at study enrollment of 43 years (IQR: 41–49) and a median age at LMD diagnosis of 51 years (IQR: 49–53). Fifty percent of included patients developed LMD in the absence of other systemic metastases. QBS demonstrated good CSF penetration 1 hour after systemic administration with a mean CSF concentration of 13.1 ng/mL, and mean CSF/plasma ratio of 2.13%. Grade IV leukopenia was observed in 40% of patients. Three patients experienced serious adverse events attributed to QBS72S, the most significant of which was cerebral edema. Median follow-up was 15 months (range: 5-22). Progression-free survival rates at 1, 3, and 6 months were 70%, 20%, and 20%, respectively. Estimated overall survival rates at 1, 3, and 6 months were 90%, 60%, and 40%, respectively. Three patients demonstrated radiographic response or stability on QBS72S, accompanied with improvement in physical and neurologic symptoms in two cases. There was no observable relationship between radiographic response/stability and QBS72 CSF/plasma ratio or LAT1 expression. Overall, QBS72S was reliably detected in CSF, well tolerated, and showed long term (six- and eight-month) radiographic improvement or stability in two patients. These findings support further investigation into QBS72S as a targeted therapy for LMD, addressing a critical unmet need in metastatic breast cancer.