373MO - Delivery and activity of SN-38 by sacituzumab govitecan in CNS tumours

Background

Sacituzumab Govitecan (SG, TRODELVY™) is unique as 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, making the drug accessible to surrounding tumor cells. The payload, SN-38, is a topoisomerase inhibitor which crosses the blood-brain barrier and is a drug partner in CNS regimens. We have observed SG activity in intracranial xenograft models. We therefore hypothesized that SG would achieve therapeutically relevant concentration of SN-38 within the CNS.

Methods

We initiated 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. Tumor and corresponding serum were collected intra-operatively. Total SN-38 concentrations were analyzed via ultrahigh-performance liquid chromatography−high resolution 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 14 patients have been treated, including 7 BCBM and 7 rGBM. No new safety signals have been observed. 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, we have observed 2 partial responses by RANO criteria within the brain from each group (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. The early intracranial responses are encouraging and will be further evaluated in the Southwest Oncology Group S2007 study.

Clinical trial identification

NCT03995706.

Editorial acknowledgement

Legal entity responsible for the study

Mays Cancer Center at UT Health San Antonio.

Funding

Mays Cancer Center and Kolitz Endowment.

Disclosure

All authors have declared no conflicts of interest.