Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial

Henriette U. Balinda, William J. Kelly, Virginia G. Kaklamani, Kate I. Lathrop, Marcela Mazo Canola, Pegah Ghamasaee, Gangadhara R. Sareddy, Joel Michalek, Andrea R. Gilbert, Prathibha Surapaneni, Stefano Tiziani, Renu Pandey, Jennifer Chiou, Alessia Lodi, John R. Floyd and Andrew J. Brenner ()
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Henriette U. Balinda: Mays Cancer Center at UT Health San Antonio
William J. Kelly: Mays Cancer Center at UT Health San Antonio
Virginia G. Kaklamani: Mays Cancer Center at UT Health San Antonio
Kate I. Lathrop: Mays Cancer Center at UT Health San Antonio
Marcela Mazo Canola: Mays Cancer Center at UT Health San Antonio
Pegah Ghamasaee: University of Texas Health Science Center at San Antonio
Gangadhara R. Sareddy: Mays Cancer Center at UT Health San Antonio
Joel Michalek: University of Texas Health Science Center at San Antonio
Andrea R. Gilbert: University of Texas Health San Antonio
Prathibha Surapaneni: START Center for Cancer Care
Stefano Tiziani: The University of Texas at Austin
Renu Pandey: The University of Texas at Austin
Jennifer Chiou: The University of Texas at Austin
Alessia Lodi: The University of Texas at Austin
John R. Floyd: University of Texas Health Science Center at San Antonio
Andrew J. Brenner: Mays Cancer Center at UT Health San Antonio

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .

Date: 2024
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DOI: 10.1038/s41467-024-50558-9

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