Abstract PD13-05: Delivery and activity of SN-38 by sacituzumab govitecan in breast cancer brain metastases

Abstract

Abstract BACKGROUND: Sacituzumab Govitecan (SG, TRODELVY™) is an FDA approved antibody drug conjugate for treatment of metastatic triple negative breast cancer (TNBC). SG has payload and linker characteristics preferable for CNS delivery including a pH hydrolysable, a payload (SN-38) that is the active 1000-fold more potent than the parent compound CPT-11 and crosses the blood brain barrier. Our preliminary data showed SG activity in intracranial xenografts leading to our hypothesis that SG would achieve concentration of SN-38 within the breast cancer brain metastases (BCBM) that would be therapeutically relevant. METHODS: We undertook a single center, prospective, window of opportunity trial (NCT03995706) to examine the concentrations of SG, SN-38, and SN-38G in tumors patients undergoing craniotomy for BCBM (n=20) or recurrent glioblastoma (rGBM, n=10). A single dose of SG was administered at 10mg/kg IV the day prior to craniotomy. Tumor was collected and [SN-38] was analyzed via mass spectrometry (UHPLC-HRMS). following recovery patients resumed SG at 10mg/kg IV days 1 and 8 of 21 day cycle and were assessed for response or progression every third cycle by MRI. RESULTS: To date 21 patients have been treated, including 11 BCBM and 10 rGBM. UHPLC-HRMS analysis was performed in the first 10 tumors (n=4 and 6 respectively). For BCBM, total concentration of SN-38 varied from 173nM to 1160nM, with a mean concentration of 626nM. All GBM patients had residual measurable disease and 4 breast patients had measurable disease. With a median follow-up of 12 weeks from the first postoperative cycle in the first 14 patients, 2 partial responses from each group were observed (ORR of 28% and 50% at 12 weeks respectively). Updated results will be presented. CONCLUSIONS: SG achieves therapeutically relevant concentrations of SN-38 at 150-fold mean IC50s for BCBM. Early intracranial responses are encouraging and merit further evaluation. A multi-center trial of SG for HER2 negative BCBM (SWOG S2007) will be enrolling soon. Citation Format: Andrew J Brenner, Renu Pandey, Jennifer Chiou, John Floyd, Prathiba Surapreneni, Virginia Kaklamani, Kate Lathrop, Richard Crownover, Stefano Tiziani. Delivery and activity of SN-38 by sacituzumab govitecan in breast cancer brain metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-05.