777P - Targeting cadherin-6 in epithelial ovarian cancer: Clinical significance of its expression and efficacy of raludotatug deruxtecan (R-DXd) in patient-derived cell models

Background

Cadherin-6 (CDH6) is a transmembrane glycoprotein, whose aberrant expression has been reported in several human carcinomas. Raludotatug deruxtecan（R-DXd） is an antibody-drug conjugate (ADC) targeting CDH6 with a topoisomerase I inhibitor (DXd) as a payload which is being developed for several malignancies, including epithelial ovarian cancer (EOC). Our aim was to understand the clinical significance of CDH6 expression in EOC and investigate the efficacy and specificity of R-DXd in EOC using patient-derived cell (PDC) models.

Methods

We performed immunohistochemical staining (IHC) for CDH6 in 232 EOC surgical samples and 23 ascites cell blocks. CDH6 IHC was scored for intensity and percent tumor cell staining. A score greater than or equal to 1+ intensity in ≥10% of tumor cells was defined as positive. The in vitro cytotoxicity and specificity of DS-6000a were evaluated in PDC models of EOC in 3-dimensinal (3D) cell culture using a luminescence-based 3D cell viability assay.

Results

A total of 117 (64.6%) of 181 patients tested positive for CDH6 expression in archival specimens from primary surgery. CDH6 expression was more frequently observed in high-grade serous carcinomas (89.0%, p < 0.0001). CDH6-positive patients showed shorter overall survival than CDH6-negative patients (p = 0.0006). 38 of the 51 (74.5%) tumors and 15 of the 23 (65.2%) ascites cells specimens from patients with recurrent disease tested positive for CDH6, respectively. Recurrent tumors had higher CDH6 scores than tumors at primary surgery, using 24 paired samples (p = 0.0039). R-DXd, DXd (free payload), control ADC and anti-CDH6 naked antibody were tested for their cytotoxicity in two CDH6-positive and two CDH6-negative PDC models. R-DXd showed significant cell growth inhibitory effect against both CDH6-positive but not in either CDH6-negative PDC models. DXd demonstrated cytotoxicity in all PDC models, regardless of CDH6 expression, whereas control ADC and anti-CDH6 naked antibody showed no growth inhibitory effects.

Conclusions

CDH6 is an attractive target for EOC and R-DXd is a promising agent for the treatment of CDH6-expressing EOC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.