Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan.

Abstract

e17028 Background: Recurrent disseminated cervical cancer is a discouraging clinical entity with 1-year survival rates between 10-15%, and development of novel, effective treatments remains an unmet medical need. We investigated the preclinical efficacy of IMMU-132 (sacituzumab govitecan), an antibody-drug conjugate (ADC) comprised of a humanized anti-trophoblast-cell-surface-antigen (Trop-2) antibody (hRS7), conjugated with a hydrolysable linker to the active metabolite of irinotecan (SN-38), against Trop-2 positive primary cervical cancer cell lines and mouse xenografts. Methods: Trop-2 expression was evaluated in 151 cervical tumors and 5 primary tumor cell lines by immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and flow cytometry. Cervical cancer cell viability against IMMU-132, non-targeting control ADC, and naked antibody (hRS7 IgG) was evaluated using flow-cytometry-based assays after 48-72 hours of incubation at a concentration of 0.05, 0.5, 1, 2, 4, and 10 nM of each agent. In vivo antitumor activity was tested in xenograft models with 3+ Trop-2 expression. Results: Out of 151 cervical tumors, 123 were squamous cell carcinoma (SCC), 26 were adenosquamous/adenocarcinoma, 1 was neuroendocrine carcinoma, and 1 was clear cell carcinoma. Strong diffuse staining was seen in 61% (75/123) of SCCs, and 92% (24/26) of adenocarcinoma/adenosquamous cancers. The neuroendocrine carcinoma was also strongly positive, while there was no staining in the clear cell carcinoma. Four out of five (80%) primary cervical cancer cell lines evaluated overexpressed Trop-2 as determined by RT-PCR and flow cytometry. Trop-2 positive cell lines showed high sensitivity to IMMU-132 in vitro, with IC50-values in the range of 0.18 to 0.26 nM ( P= 0.02). In contrast, a Trop-2 negative cervical cell line was highly resistant to the ADC with similar IC50 for IMMU-132 and control ADC. In xenografts, twice-weekly intravenous administration of IMMU-132 for three weeks demonstrated significant tumor growth inhibition compared to controls ( P≤0.001). Overall survival was significantly increased in mice treated with IMMU-132 ( P= 0.014) when compared to naked antibody and ADC-control groups. Conclusions: Sacituzumab govitecan may represent a novel class of active drugs for cervical cancers overexpressing Trop-2. Clinical trials are warranted.