786P - Antitumor activity of farletuzumab ecteribulin in a panel of endometrial cancer patient-derived xenografts with four different molecular subtypes

Background

Endometrial cancer (EC) is the most common gynecological malignancy, and treatments based on its molecular subtypes have recently been proposed. Patient-derived xenografts (PDX) are models that preserve the heterogeneity and histology of tumors, and may mimic the effects of drugs in patients. Here, we report a preclinical study of farletuzumab ecteribulin (MORAb-202, FZEC), a novel antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα), using a panel of EC-PDX models with different molecular subtypes.

Methods

We developed a panel of 36 EC-PDX models with four molecular subtypes. We investigated FRα expression based on the H-scores. The antitumor activity of FZEC was evaluated in 24 EC-PDX models, including three POLE-mutated, two MSI-H hypermutated, 11 copy number (CN)-high, and eight CN-low tumors, with various levels of FRα expression in the four treatment groups (control saline, FZEC 5 mg/kg, 12.5 mg/kg, and eribulin 3.2 mg/kg, n=6 in each group). Each drug was administered intravenously, and tumor size was measured twice a week for a 21-day observation period. The intratumoral distribution of eribulin was periodically visualized using an anti-eribulin antibody with the Opal multi-fluorescent staining system.

Results

The median H-scores of FRα expression in the 36 PDX and original tumors were 9.5 (0–184) and 74 (11-184), respectively, indicating a trend toward decreased FRA expression on the PDX. There was no relationship between FRA expression and molecular subtypes. The efficacy of FZEC was evaluated using 24 EC-PDX models. Antitumour activity was observed across all four molecular subtypes. Tumor shrinkage was associated with FRα expression in FZEC 5 mg/kg group, whereas an overall FRA-independent tumor shrinkage was observed in FZEC 12.5 mg/kg and eribulin 3.2 mg/kg groups. Intratumoral imaging analysis using tumors on day 21st showed an association between the antitumor effect and intratumoral accumulation of eribulin.

Conclusions

These results suggest that FZEC may be a promising treatment for FRα-expressing EC of all four molecular subtypes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

National Cancer Center, Tokyo, Japan Saitama Medical University International Medical Center, Saitama, Japan.

Funding

Eisai.

Disclosure

K. Hasegawa: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Takeda, Chugai, Genmab, Kaken, Eisai, Sanofi, GSK; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Funding, contracted research: MSD, Ono, Daiichi Sankyo, Eisai, Takeda. S. Yagishita: Financial Interests, Personal, Invited Speaker: LSI Medience. T. Nishikawa: Financial Interests, Personal, Other, Speaker's Bureau: Eisai, AstraZeneca, Takeda Pharmaceutical Company, MSD, Chugai Pharmaceutical Company, Sanofi; Financial Interests, Institutional, Other, Research funding: Daiichi Sankyo; Financial Interests, Institutional, Other, Research Funding: AstraZeneca. K. Yonemori: Financial Interests, Personal, Advisory Board: Eisai, AstraZeneca, Sanofi, Genmab, Gilead, OncoXerna, Takeda, Novartis, MSD; Financial Interests, Personal, Invited Speaker: Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR Pharma, MSD, Ono, BMS, Boehringer Ingerleim, Daiichi Sankyo, Bayer, Jansen, Sanofi; Financial Interests, Institutional, Local PI: MSD, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seagen, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirrin, Nihon Kayaku, Haihe. K. Furuuchi: Financial Interests, Personal, Full or part-time Employment: Eisai Inc. T. Uenaka: Financial Interests, Personal, Full or part-time Employment: Eisai Inc., Eisai Co., Ltd.; Financial Interests, Personal, Stocks/Shares: Eisai Co., Ltd. A. Hamada: Financial Interests, Funding: Eli Lilly, AstraZeneca, Boehringer Ingelheim, Eisai, Sysmex, Chordia therapeutics, Helios, Konica Minolta. All other authors have declared no conflicts of interest.