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

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-paraffinedembedded (FFPE) CS by immunohistochemistry and 9 primary CS cell-lines by flowcytometry. 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.

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial

“…6,45 These data are in line with earlier preclinical studies of uterine, ovarian, and endometrial adenocarcinoma models, all of which overexpress Trop-2, where SG demonstrated a significant in vitro cytotoxic effect on primary Trop-2-positive cell lines, a significant bystander killing effect in the tumor microenvironment, and antitumor effects in Trop-2-positive xenograft models. [46][47][48] A study of SG in endometrial carcinoma is underway in Trop-2-enriched patients to determine whether additional efficacy may be achieved by selecting patients with high Trop-2-expressing tumors (NCT04251416).…”

Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer

“…6,[8][9][10] Its proprietary linker also allows SN-38 to be liberated in the tumor microenvironment, enabling antitumor effects (bystander effect) without prerequisite internalization and enzymatic cleavage of SN-38 from the anti-Trop-2 antibody. 6,8,11 As BRCA1 or BRCA2 (BRCA1/2) confer a deficiency in homologous recombination repair of double-stranded DNA breaks, there is interest in BRCA1/2 as a potential biomarker of response for therapy regimens that target DNA damage, particularly for TNBC. 12 Approximately 15% of patients with TNBC have germline BRCA mutations, a higher prevalence compared with other breast cancer subtypes.…”

An overview of antibody–drug conjugates in oncological practice

“…Based on results of phase II trials in small cell lung carcinoma and non-small cell lung carcinoma, SG also gained Fast Tract designation from the US FDA for these conditions. Overall, SG holds great promise in the field of ADCs, as supported by SG data of remarkable preclinical potency in tumors, including ovarian, 74 uterine, 75 and cervical 76 cancers.…”