Antitumor Effect of Farletuzumab Ecteribulin in Molecular Subtypes of Endometrial Cancer Patient-Derived Xenograft...

Endometrial cancer represents a significant health burden globally, particularly in postmenopausal women. Current treatment options for advanced-stage endometrial cancer remain limited, emphasizing the need for novel therapeutic strategies. This study aimed to investigate farletuzumab ecteribulin (FZEC), an antibody-drug conjugate targeting folate receptor α (FRα), as a potential new therapeutic agent for endometrial cancer. We utilized a panel of 22 patient-derived xenograft (PDX) models, representing various histologic and molecular subtypes of endometrial cancer with different levels of FRα expression, to evaluate the antitumor effect of FZEC. FZEC was administered intravenously at doses of 5 and 12.5 mg/kg on day 0. Intratumoral accumulation of eribulin, the payload of FZEC, was visualized using phosphor-integrated dot imaging. FZEC demonstrated dose-dependent antitumor effects across the endometrial cancer-PDX panel. At 5 mg/kg, the FZEC efficacy was associated with FRα expression, with 100% of FRα 3+ models exhibiting tumor shrinkage compared with 33.3% of FRα-negative models. FZEC also demonstrated broad activity across both histologic and molecular subtypes. Intratumoral eribulin accumulation was highly correlated with antitumor effects, even in models with low FRα expression. Follow-up studies confirmed FRα-dependent antitumor effects while also indicating potential FRα-independent mechanisms of action. FZEC demonstrated a robust antitumor effect against the FRα-high endometrial cancer-PDX models with significant antitumor effects also observed, even in FRα-low or FRα-negative models. Notably, intratumoral eribulin accumulation exhibited a stronger correlation with efficacy than with FRα expression alone. These findings support further clinical development of FZEC for endometrial cancer treatment and highlight the complexity of the mechanisms of action of antibody-drug conjugates.