Preclinical activity of sacituzumab govitecan (IMMU-132) in uterine and ovarian carcinosarcomas

Abstract

// Salvatore Lopez 1 , 2 , 3 , Emanuele Perrone 1 , Stefania Bellone 1 , Elena Bonazzoli 1 , Burak Zeybek 1 , Chanhee Han 1 , Joan Tymon-Rosario 1 , Gary Altwerger 1 , Gulden Menderes 1 , Anna Bianchi 1 , Luca Zammataro 1 , Aranzazu Manzano 1 , Paola Manara 1 , Elena Ratner 1 , Dan-Arin Silasi 1 , Gloria S. Huang 1 , Masoud Azodi 1 , Peter E. Schwartz 1 , Francesco Raspagliesi 3 , Roberto Angioli 4 , Natalia Buza 5 , Pei Hui 5 , Heather M. Bond 6 and Alessandro D. Santin 1 1 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA 2 Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy 3 Department of Gynecologic Oncology, IRCCS National Cancer Institute, Milan, Italy 4 University Campus Bio Medico of Rome, Department of Obstetrics and Gynecology, Rome, Italy 5 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA 6 Department of Clinical and Experimental Medicine, Laboratory of Molecular Haematopoiesis and Stem Cell Biology, University “Magna Græcia”, Catanzaro, Italy Correspondence to: Alessandro D. Santin, email: alessandro.santin@yale.edu Keywords: sacituzumab govitecan; IMMU-132; uterine carcinosarcoma; trop-2 Received: July 19, 2019     Accepted: October 26, 2019     Published: February 04, 2020 ABSTRACT Background Uterine and ovarian carcinosarcomas (CS) are rare cancers with poor prognosis. Sacituzumab-govitecan (SG) is a new class of antibody-drug-conjugate (ADC) targeting the human-trophoblast-cell-surface marker (Trop-2) conjugated with the active metabolite of irinotecan (SN-38). We evaluated the efficacy of SG against biologically aggressive CS. Methods Trop-2 expression was evaluated in 10 formalin-fixed-paraffined-embedded (FFPE) CS by immunohistochemistry and 9 primary CS cell-lines by flow-cytometry. One Trop-2 low/negative (SARARK14) and two Trop-2 positive (SARARK4, SARARK9) cell-lines were tested in cell-viability assays . The in vivo antitumor activity of SG was tested in xenografts models (ie, SARARK9) with strong Trop-2 expression. Results Strong/diffuse staining was seen in 30% (3/10) of FFPE tumors and 33% (3/9) of primary CS cell lines. Trop-2 positive cell-lines (SARARK4, SARARK9) showed higher sensitivity to SG in vitro when compared to Trop-2 low/negative (SARARK14) cell lines. In xenografts, twice-weekly intravenous administration of SG for three weeks showed a significant tumor growth inhibition when compared to control, to ADC control and to the naked AB (p=0.004, p=0.007 and p=0.0007, respectively). SG significantly improved overall survival at 90 days when compared to control groups (p<0.0001). Conclusion SG may represent a novel class of active drugs for carcinosarcomas patients overexpressing Trop-2.