The results of a prospective window-of-opportunity trial at the University of Texas Health Science Center at San Antonio (UT Health San Antonio) suggest an antibody-drug conjugate (ADC) treatment that has been effective in treating breast cancer may also show promise in addressing breast cancer with brain metastases (BCBM), or recurrent glioblastoma (rGBM).
The window trial, in which patients undergoing craniotomy for BCBM or rGBM agreed to receive the drug Sacituzumab Govitecan (SG) before undergoing surgery, found that the novel treatment was well tolerated and showed signs of effectiveness for those whose breast cancer had progressed to brain tumors. The researchers believe the newly reported data support ongoing investigation in a Phase II clinical trial of the drug in recurrent glioblastoma.
“We knew that the drug has been effective in the treatment of breast cancer, but its usefulness in treatment of resulting brain tumors has been unclear,” said Andrew J. Brenner, MD, PhD, professor and chair of neuro-oncology research with Mays Cancer Center at UT Health San Antonio. “Our trial, however, revealed that it could achieve concentrations of inhibitors inside the tumors sufficient to benefit patients, and with minimal side effects, which is very promising for new therapy.”
Brenner, who also is clinical investigator for the Institute for Drug Development at UT Health San Antonio and co-leader of its Experimental and Development Therapeutics Program, is lead author of the team’s report in Nature Communications, titled “Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial.” In their paper the team concluded, “SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS.”
Brain tumors originating from breast cancer are frequent, and treatment for these tumors typically involve surgery, radiotherapy and systemic therapies, though these measures often are unsuccessful. “The prognosis for patients with malignant brain tumors is grim,” the authors wrote. “In terms of disease burden, brain tumors of breast origin are frequent, accounting for 15 to 25% of patients with stage IV breast cancer.”
About half of all women with the aggressive and advanced triple-negative breast cancer (TNBC) will be diagnosed with brain metastases, and the prognosis is poor, with a median overall survival of just more than seven months. Similarly, glioblastoma multiforme is the most common primary brain malignancy in adults, representing half of such tumors. It also is the most aggressive primary brain tumor, with a median survival of only 20.9 months despite surgery, radiotherapy, chemotherapy and tumor-treating regimens.
For those reasons, there has been an unmet need to address breast cancer with brain metastasis and recurrent glioblastoma multiforme, and treatment of both primary and secondary brain tumors is limited by many factors.
Sacituzumab Govitecan (SG) is a known ADC developed as a targeted cancer therapy that, unlike chemotherapy, is designed to target and kill tumor cells while sparing healthy cells. The drug has been found effective in patients expressing TROP-2, a membrane protein found in many tumors. “Trop-2, also known as trophoblast cell-surface antigen-2, is a cell surface glycoprotein that is differentially expressed in several epithelial tumors,” the team further explained. “Trop-2 is not expressed by normal brain tissue but 95% of GBM samples show moderate to intense staining as assessed by immunohistochemistry.”
Sacituzumab Govitecan targets Trop-2 for the selective delivery of SN-38 to tumors. The ADC consists of a humanized antibody (hRS7) that recognizes Trop-2, and releases SN-38 at the tumor site. “SN-38 is a topoisomerase inhibitor and the active metabolite of irinotecan,” the investigators commented.
The trial at UT Health San Antonio enrolled 25 patients aged 18 or older who had been diagnosed with breast cancer with brain metastases or recurrent glioblastoma. Each received a single intravenous dose of SG one day before tumor-tissue removal and continuing on days one and eight of 21-day cycles following recovery. The timeframes were eight months for patients with breast cancer with brain metastases and two months for those with recurrent glioblastoma. The researchers discovered significant penetration of the drug SN-38 inside the tumors, without unexpected adverse effects for the patients, and with “promising clinical signs of efficacy.”
“… we report the results of a phase 0 window-of-opportunity study of patients with BCBM and rGBM, showing that SG could achieve intratumoral concentrations of SN-38 sufficient for therapeutic benefit in patients with brain metastases from breast cancer and recurrent glioblastoma,” they concluded.
The team suggests their results support an ongoing Phase II study with SG. “We currently are in the interim analysis stage of that Phase II trial, which enrolled 20 patients at UT Health San Antonio, Cleveland Clinic and Texas Oncology in Austin,” said William Kelly, MD, assistant professor of hematology and oncology at Mays Cancer Center, and principal investigator for the Phase II trial. “We expect it will shed further light on the possible effectiveness of SG in treating glioblastoma.”
