Sacituzumab govitecan plus platinum-based chemotherapy mediates significant antitumor effects in triple-negative breast, urinary bladder, and small-cell lung carcinomas

// Thomas M. Cardillo 1 , 2 , * , Maria B. Zalath 1 , * , Roberto Arrojo 1 , * , Robert M. Sharkey 1 , * , Serengulam V. Govindan 1 , * , Chien-Hsing Chang 1 , * and David M. Goldenberg 1 , 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 Copyright: © 2024 Cardillo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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.