Abstract B107: Antitumor activity of new antibody-drug conjugate with eribulin in triple-negative breast cancer PDX
Authors: Hillairet de Boisferon Marc , Mignard Caroline , Durix Coralie , Uenaka Toshimitsu , Rybinski Katherine , Cheng Xin , Furuuchi Keiji , Albone Eart 
Published: August 2018

Trastuzumab-emtansine (T-DM1) is an ADC that combines the HER2-targeting properties of trastuzumab with intracellular delivery of DM1 (a highly potent derivative of the anti-microtubule agent maytansine). A new biomarker of recent interest in the cancer field is folate receptor alpha (FRA), a membrane-bound protein with high affinity for binding and transporting folate into cells. Overexpression of FRA may confer a growth advantage to tumors by increasing folate uptake and affect cell proliferation via alternative cell signaling pathways. FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue, including TNBC. Due to an absence of potential targeted therapy for this breast cancer subtype, the finding that a significant number of TNBCs express abundant FRA suggests an important population of patients may benefit from FRA-targeting therapy. Eighty-five percent of preclinical agents entering oncology clinical trials fail to demonstrate sufficient safety or efficacy to gain regulatory approval. This failure rate shows a weak understanding of the complexity of human cancer, the continued limitations of the predictive value of existing preclinical models, and the scale at which cancer models are interrogated in the preclinical setting. There is a need for new experimental models that better replicate the diversity of human tumor biology in a preclinical setting. It is now evidenced that PDXs recapitulate human tumor biology and predict patient drug response by directly comparing drug responses in patients and their corresponding xenografts. To extend such observations to a greater number of human cancers, we have generated in collaboration with Eisai an extensive collection of breast PDXs. In this study, MORAb-202, a novel folate receptor-targeting eribulin conjugate created through a Morphotek and Eisai collaboration, was tested in FRA-expressing TNBC PDXs. Compared to free eribulin, MORAb-202 showed higher and specific antitumor activity on FRA-positive PDXs. When injected once, MORAb-202 at 5 mg/kg (0.1 mg/kg eq eribulin) showed a treatment group/control group percent (T/C %) between 4 to 17%, whereas eribulin injected at 0.1 mg/kg following the same equivalent dose and schedule of administration showed a T/C % between 74 to 93%. On non-FRA-expressing PDXs, antitumor activities of MORAb-202 and eribulin were similar. Interestingly, to find similar antitumor activity, the dose of eribulin without vectorization should be enhanced to 32-fold compared to targeted eribulin. At this dose of eribulin, close to the maximum tolerated dose, a tumor relapse is observed (100%), whereas no relapse was observed for mice treated with MORAb-202. These encouraging results lead to a proof of concept of the use of MORAb-202 in TNBC.

Citation Format: Marc Hillairet de Boisferon, Caroline Mignard, Coralie Durix, Toshimitsu Uenaka, Katherine Rybinski, Xin Cheng, Keiji Furuuchi, Eart Albone. Antitumor activity of new antibody-drug conjugate with eribulin in triple-negative breast cancer PDX [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B107.