A clinical trial (NCT03995706) studying the extent by which sacituzumab govitecan (Trodelvy™; Immunomedics) is able to get into the brain and treat patients with breast cancer that has metastasized to the brain (BMBC) and recurrent glioblastoma (rGBM), shows encouraging results.
About 10 to 15% of women with stage IV breast cancer eventually develop brain metastases (BMBC) which is the second most common cause of central nervous system (CNS) metastases. However, in the majority of women, their cancer has already metastasized to the bones, liver, or lung. But in about 17% of cases in this patient population, the brain is the only site of metastasis.
Overall, patients with more aggressive subtypes of cancer triple-negative breast cancer (TNBC) or human epidermal growth factor receptor 2 (HER2)-positive cancers have a particularly high rate of CNS metastases. Other risk factors for the development of CNS disease include young age, African American ancestry, visceral involvement, and high-grade disease.
According to the National Cancer Institute (NCI), an estimated 23,890 Americans will be diagnosed with brain cancer in 2020 and about 18,020 people will die from the disease in the U.S. this year. Among the numerous brain tumor types, glioblastoma (GBM) is the most aggressive, with median progression-free survival (PFS) and median overall survival (OS) from diagnosis of 6.2-7.5 months and 14.6-16.7 months, respectively, having been reported in clinical trials. 
For patients with recurrent GBM, chemotherapy regimens are associated with overall response rates of 4-9%, 6‑month PFS of 10-19%, and median OS of 5-10 months. 
Sacituzumab govitecan is an antibody-drug conjugate that includes a humanized antibody (hRS7) against tumor-associated calcium signal transducer 2 (TACSTD2 or TROP2) linked to the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), a topoisomerase I inhibitor. The antibody moiety of sacituzumab govitecan selectively binds to TROP2. After internalization and proteolytic cleavage, SN-38 selectively stabilizes topoisomerase I-DNA covalent complexes, resulting in DNA breaks that inhibit DNA replication and trigger apoptosis.
In April 2020 the drug received accelerated approval in the United States for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease and is undergoing phase III development for breast cancer and phase II development for urothelial cancer. Sacituzumab govitecan is also being explored for brain metastases, glioblastoma, endometrial cancer, and prostate cancer.
Patients diagnosed with BMBC or rGBM were enrolled in a single-center clinical study to receive a single intravenous dose of sacituzumab govitecan at 10 mg/kg one day before surgical resection. Tumor and corresponding serum were collected during surgery to measure their levels of SN-38 and its metabolites. Following recovery, patients resumed Trodelvy treatment at 10 mg/kg on days 1 and 8 of 21-day cycles and were assessed for responses by MRI every third cycle using response assessment in neuro-oncology (RANO) criteria.
The results of the study include partial responses in a small cohort of patients with brain metastasis from breast cancer and recurrent glioblastoma.
Sacituzumab govitecan delivered 150-fold and 40-fold the 50% inhibitory concentration (IC50) of SN-38 for BMBC and rGBM, respectively, and produced partial responses in both cohorts of brain cancer patients.
“These early intracranial responses are very encouraging signs of sacituzumab govitecan’s activity in central nervous system (CNS) tumors as previously observed in preclinical models,” explained Andrew J. Brenner, M.D. Ph.D., Clinical Investigator, Institute for Drug Development; Co-Leader, Experimental and Developmental Therapeutics Program; S & B Kolitz/CTRC-Zachry Endowed Chair in Neuro-Oncology Research, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, who reported the results in a mini oral session on CNS tumors at the European Society of Medical Oncology (ESMO) Virtual Congress 2020. 
“With a hydrolyzable linker that allows SN-38 to be released at the tumor site and given that SN-38 freely crosses the blood-brain barrier and is active in the nanomolar range for most cancer cells, including triple-negative breast cancer (TNBC) and GBM, sacituzumab govitecan has the prerequisite ability to deliver therapeutically relevant concentrations of SN-38 across an undisrupted vasculature. The early clinical results in patients with neoplastic involvement of the brain warrant further development of Trodelvy in these aggressive and lethal cancers,” Brenner continued.
At the time of data cutoff, 19 patients (7 BMBC and 12 rGBM) were enrolled in the study. Key clinical data from evaluable patients are summarized below. No new safety signals were observed.
“Brain metastasis is a significant concern in patients with TNBC, and we are very encouraged by these early-stage study results,” stated Loretta M. Itri, M.D., Chief Medical Officer of Immunomedics.
“Additionally, given that GBM is a disease with great unmet need, we are working in close collaboration with Brenner and others, including the Southwestern Oncology Group, to design programs that could potentially elucidate the role of Trodelvy in the management of BMBC and rGBM,” she added
Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0. NCT03995706
Highlights of Prescribing Information
Sacituzumab govitecan (Trodelvy™; Immunomedics) [Prescribing Information]
 Pandey R, Gruslova A, Chiou J, Brenner AJ, Tiziani S. Stable Isotope Dilution LC-HRMS Assay To Determine Free SN-38, Total SN-38, and SN-38G in a Tumor Xenograft Model after Intravenous Administration of Antibody-Drug Conjugate (Sacituzumab Govitecan). Anal Chem. 2020;92(1):1260-1267. doi:10.1021/acs.analchem.9b04419
 Cancer Stat Facts: Brain and Other Nervous System Cancer. National Cancer Institute. Online. last accessed on September 18, 2020.
 Stupp R, Mason WP, van den Bent MJ, et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.
 Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370 (8):699-708.
 Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32):4085-4091.
 Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370 (8):709-722.
 Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled in phase II clinical trials. J. Clin. Oncol. 17, 2572–2578 (1999).
 van den Bent MJ, Brandes AA, Rampling R, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J. Clin. Oncol. 27, 1268–1274 (2009).
 Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J. Clin. Oncol. 31, 3212–3218 (2013).
 Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J. Clin. Oncol. 28, 1168–1174 (2010).
 Taal W, Oosterkamp HM, Walenkamp AME, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomized controlled phase 2 trial. Lancet Oncol. 15, 943–953 (2014).
Featured image: ESMO annual congress 2017. Photo courtesy: European Society of Medical Oncology (ESMO). Used with permission.
An edited version of this article was published in Onco’Zine.