Sacituzumab Govitecan Shows Preliminary Activity in Patients With Brain Mets, GBM

Neoadjuvant/adjuvant sacituzumab govitecan showed encouraging intratumoral concentrations in patients with brain metastases as well as glioblastoma.

The antibody-drug conjugate (ADC), sacituzumab govitecan (Trodelvy), given in the neoadjuvant and adjuvant settings, displayed promising preliminary activity in patients undergoing craniotomy for breast cancer with brain metastases or those with recurrent glioblastoma (GBM), according to a phase 0 window-of-opportunity study (NCT03995706) published in Nature Communications.

­Data showedthat thetotal median SN-38 in postsurgical tissue was 197.3 ng/g and 104.5 ng/g for the breast cancer and GBM cohorts, respectively. Additionally, the total median SN-38 in serum analysis was 2462.4 ng/ml in BCBM and 2465.7 ng/ml in rGBM. For the breast cancer cohort, the median progression-free survival (PFS) was 8 months (range 2-26.5) and overall survival (OS) was 35.2 months (range, 2.7-37); the median PFS and OS was 2 months (range, 0.5-13.2) and 9.5 months (range, 1.0-28.0), respectively, in the GBM cohort.

“[I]n this phase 0 study of patients with brain metastasis from breast cancer and recurrent glioblastoma, presurgical sacituzumab govitecan given preoperatively and as adjuvant therapy to surgery, was determined to be well tolerated with robust efficacy signals,” lead study author Henriette U. Balinda, MSc, PhD, research scientist at the Mays Cancer Center at the University of Texas Health San Antonio, and coinvestigators wrote in the study. “Most importantly, encouraging intratumoral concentrations were achieved. This data supports the ongoing investigation in a phase 2 clinical trial (NCT04559230) of this drug in recurrent glioblastoma.”

Investigators enrolled 25 patients from August 16, 2019 to October 22, 2020 to receive sacituzumab govitecan; patients either had breast cancer with brain metastases (n = 13) or glioblastoma (n = 12). Patients received 10 mg/kg sacituzumab govitecan intravenously the day before craniotomy; upon recovery, sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles. Initial infusion occurred over 3 hours, with 1 to 2 hour–shortening allowance for subsequent infusions if tolerated well.

Pegfilgrastim (Neulasta) was given on the first day of surgery, and depending on absolute neutrophil count, was given day 8 of each cycle. Patients were premedicated with acetaminophen, diphenhydramine, and dexamethasone across both cohorts. Treatment continued until progressive disease, unacceptable treatment-related adverse event (TRAE), or study withdrawal.

The primary end point was SN-38 concentration in serum intracranially and in cerebrospinal fluid (CSF). Secondary end points include PFS, OS, and safety for patients from postsurgical treatment. An unplanned exploratory end point was overall response rate (ORR).

ORR was 38% for the breast cancer and 29% for GBM groups, respectively. Median SN-38 levels in serum analysis were 2462.4 ng/ml (range, 1266.9-5659.6; IQR, 2483.2) in the breast cancer cohort and 2465.7 ng/ml (range, 115.0-5363.1; IQR, 1992.9) in the GBM cohort. Furthermore, the range for SN-38 levels for tumor tissue were 86.5 to 652.0 ng/ml (IQR, 230.1) in the breast cancer cohort and 8.6 ng/g to 259.1ng/g (IQR, 182.7) in the glioblastoma group.

Safety analysis revealed the most common grade 1/2 AEs were fatigue (60%), diarrhea (52%), alopecia (44%), headache (40%), neutropenia (40%), and nausea (36%). Grade 3 or higher AEs included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). There was 1 grade 4 AE, which was neutropenia, and no grade 5 AEs occurred.

Reference

Balinda HU, Kelly WJ, Kaklamani VG, et al. Sacituzumab govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial. Nat Commun. 2024;15. doi:10.1038/s41467-024-50558-9