Abstract 3370: Anti-tumor activity of Debio 0123 in combination with sacituzumab govitecan in preclinical models of breast cancer
Authors: Piggott Luke , Imedio Esteban Rodrigo , Staehli Francesco 
Published: March 2024

Abstract
Background: Debio 0123 is a WEE1 inhibitor that has previously shown significant preclinical efficacy in combination with DNA damaging agents and is currently being investigated in phase 1 clinical studies either as a monotherapy or in combination with different standard therapies. Sacituzumab govitecan (SG) is a TROP2 directed antibody-drug-conjugate (ADC) carrying an SN38 payload that has recently gained approval in TNBC and ER+ve breast cancer after demonstrating improvements in survival versus standard therapies. Despite these promising data some patients still do not respond to SG treatment, develop resistance or experience toxic side effects. Herein we present preclinical data that demonstrates Debio 0123 improves tumor response to SG in breast cancer models and provides sustained complete responses and anti-metastatic activity.
Methods: Synergy between Debio 0123 and SG was evaluated in breast cancer cell lines, with varying levels of TROP2 expression, in vitro using standard cytotoxicity assay in a matrix combination format. Efficacy of Debio 0123 and SG as monotherapies or in combination was further assessed in vivo, in both TROP2high and TROP2low subcutaneous breast cancer xenograft models at different doses.
Results: In vitro, Debio 0123 in combination with SG demonstrated synergistic tumor cell killing in all 4 breast cancer cell lines tested, at all concentrations. In vivo, TROP2high MDA-MB-468 breast cancer xenograft tumors treated with Debio 0123 at 30mg/kg QD resulted in minimal anti-tumor activity as a monotherapy but completely regressed 100% of the tumors in combination with SG. Furthermore, 40% of these complete regressions were sustained for up to 100 days post-treatment initiation. These data were then further replicated at a reduced dose of SG. In the TROP2low MDA-MB-231luc model, Debio 0123 significantly improved response to SG resulting in a 2-fold improvement in tumor growth inhibition. Additionally, combination treatment significantly inhibited metastasis of these tumors to the lung and lymph nodes as monitored by bioluminescence. Collectively, these results lead to a significant improvement in animal survival as a combination compared to either treatment as a monotherapy.
Conclusion: These results demonstrate that Debio 0123 synergizes with, and significantly improves breast cancer tumor cell response to, SG regardless of TROP2 expression levels (both in vitro and in vivo), leading to complete regressions and inhibition of metastasis. Collectively these data support Debio 0123 in combination with SG could be a potential therapeutic approach for improving responses in patients with breast cancer.
Citation Format: Luke Piggott, Esteban Rodrigo Imedio, Francesco Staehli. Anti-tumor activity of Debio 0123 in combination with sacituzumab govitecan in preclinical models of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3370.