Antitumor Effect of Farletuzumab ecteribulin in Molecular Subtypes of Endometrial Cancer Patient-Derived Xenograft Models

Abstract Endometrial cancer (EC) represents a significant health burden globally, particularly in postmenopausal women. Current treatment options for advanced-stage EC remain limited, emphasizing the need for novel therapeutic strategies. This study aimed to investigate farletuzumab ecteribulin (FZEC), an antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα), as a potential new therapeutic agent for EC. We utilized a panel of 22 patient-derived xenograft (PDX) models, representing various histological and molecular subtypes of EC with different levels of FRα expression, to evaluate the antitumor effect of FZEC. FZEC was administered intravenously at doses of 5 mg/kg 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 EC-PDX panel. At 5 mg/kg, the FZEC efficacy was associated with FRα expression, with 100% of FRα 3+ models exhibiting tumor shrinkage compared to 33.3% of FRα-negative models. FZEC also demonstrated broad activity across both histological 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 robust antitumor effect against the FRα high EC-PDX modelswith significant antitumor effects also observed, even in FRα-low or 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 EC treatment and highlight the complexity of the mechanisms of action of ADCs.