Research Papers:
Sacituzumab govitecan plus platinum-based chemotherapy mediates significant antitumor effects in triple-negative breast, urinary bladder, and small-cell lung carcinomas
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Abstract
Thomas M. Cardillo1,2,*, Maria B. Zalath1,*, Roberto Arrojo1,*, Robert M. Sharkey1,*, Serengulam V. Govindan1,*, Chien-Hsing Chang1,* and David M. Goldenberg1,3,#
1 Immunomedics, Inc., Morris Plains, NJ 07950 now acquired by Gilead Sciences, Inc., Foster City, CA 94404, USA
2 Gilead Sciences, Inc., Foster City, CA 94404, USA
3 Current address: Center for Molecular Medicine and Immunology, Mendham, NJ 07945, USA; E-mail, dmg.gscancer@att.net.
* At the time the work was conducted, all the authors were employees of Immunomedics, Inc.
# At the time the work was conducted, this author was Chairman and Chief Scientific Officer of Immunomedics, Inc., which he founded in 1982
Correspondence to:
Thomas M. Cardillo, | email: | Thomas.Cardillo1@Gilead.com |
Keywords: sacituzumab govitecan; Trop-2; SN-38; carboplatin; cisplatin
Received: July 24, 2023 Accepted: January 23, 2024 Published: February 22, 2024
ABSTRACT
Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2-directed antibody conjugated with the topoisomerase I inhibitory drug, SN-38, via a proprietary hydrolysable linker. SG has received United States Food and Drug Administration (FDA) approval to treat metastatic triple-negative breast cancer (TNBC), unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and accelerated approval for metastatic urothelial cancer. We investigated the utility of combining SG with platinum-based chemotherapeutics in TNBC, urinary bladder carcinoma (UBC), and small-cell lung carcinoma (SCLC). SG plus carboplatin or cisplatin produced additive growth-inhibitory effects in vitro that trended towards synergy. Immunoblot analysis of cell lysates suggests perturbation of the cell-cycle and a shift towards pro-apoptotic signaling evidenced by an increased Bax to Bcl-2 ratio and down-regulation of two anti-apoptotic proteins, Mcl-1 and survivin. Significant antitumor effects were observed with SG plus carboplatin in mice bearing TNBC or SCLC tumors compared to all controls (P < 0.0062 and P < 0.0017, respectively) and with SG plus cisplatin in UBC and SCLC tumor-bearing animals (P < 0.0362 and P < 0.0001, respectively). These combinations were well tolerated by the animals. Combining SG with platinum-based chemotherapeutics demonstrates the benefit in these indications and warrants further clinical investigation.
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