In vitro and in vivo activity of imgn853, an antibody–drug conjugate targeting folate receptor alpha linked to dm4, in biologically aggressive endometrial cancers

Abstract

Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRa) expression in these biologically aggressive (type II) endometrial cancers and evaluate FRa as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FRa was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRa. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/ patient-derived xenograft (PDX) models. Semiquantitative IHC analysis indicated that 41% of the USC patients overexpress FRa. Further, overexpression of FRa (i.e., 2þ) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared with control in 2þ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRa showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRa ¼ 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2þ FRa, IMGN853 treatment showed complete resolution of tumors (P < 0.001). Treatment with IMGN853 in the USC PDX model (BIO(K)1), expressing 2þ FRa, induced twofold increase in median survival (P < 0.001). IMGN853 shows impressive antitumor activity in biologically aggressive FRa 2þ uterine cancers. These preclinical data suggest that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRa may benefit from this treatment.