In Vitro and In Vivo Activity of IMGN853, an Antibody-Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers

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 (FR alpha) expression in these biologically aggressive (type II) endometrial cancers and evaluate FR alpha as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FR alpha 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 FR alpha. 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 FR alpha. Further, overexpression of FR alpha (i.e., 2+) 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 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FR alpha showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FR alpha = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FR alpha, IMGN853 treatment showed complete resolution of tumors (P < 0.001). Treatment with IMGN853 in the USC PDX model (BIO(K)1), expressing 2+ FR alpha, induced twofold increase in median survival (P < 0.001). IMGN853 shows impressive antitumor activity in biologically aggressive FR alpha 2+ uterine cancers. These preclinical data suggest that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FR alpha may benefit from this treatment. (C) 2018 AACR.