Abstract
BACKGROUND
Sacituzumab Govitecan (SG, TRODELVY™) is an antibody drug conjugate, with payload and linker characteristics preferable for CNS delivery. SG utilizes a pH hydrolysable linker, allowing SN-38 to be released at the tumor site. SN-38 is the active component of Irinotecan and 1000-fold more potent than the parent compound. We observed SG activity in intracranial xenografts and hypothesized that SG would achieve therapeutically relevant concentration of SN-38 within the CNS.
METHODS
We performed a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SG, SN-38, and SN-38G in patients undergoing craniotomy for breast cancer brain metastases (BCBM, n=10) or recurrent glioblastoma (rGBM, n=10). Patients received a single dose of SG at 10mg/kg IV the day prior to craniotomy and tumor collected. [SN-38] was analyzed via mass spectrometry (UHPLC-HRMS). Patients resumed SG 10mg/kg IV days 1 and 8 of 21 day cycle following recovery and were assessed every third cycle by MRI using RANO criteria.
RESULTS
To date 16 patients have been treated, including 8 BCBM and 8 rGBM. UHPLC-HRMS analysis was performed in the first 10 tumors (n=4 and 6 respectively). For the rGBM patients, total concentration of SN-38 varied from 93nM to 680nM, with a mean concentration of 420nM. 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).
CONCLUSIONS
SG achieves therapeutically relevant concentrations of SN-38 at 40-fold mean IC50s for GBM, and 150-fold mean IC50s for BCBM. Early intracranial responses are encouraging and merit further evaluation.