35P - The selective WEE1 inhibitor azenosertib shows synergistic anti-tumor effects in combination with topoisomerase I inhibitor-based antibody drug conjugates

Background

Azenosertib is a highly potent and selective WEE1 kinase inhibitor that induces replication stress, DNA damage and mitotic catastrophe. It has shown significant preclinical efficacy as monotherapy and in combination with DNA damaging agents. Topoisomerase I (TOP1) inhibitors interrupt DNA replication and induce DNA damage, leading to cell cycle arrest for DNA repair. Azenosertib overrides cell cycle arrest, resulting in premature mitotic entry of cells with unrepaired DNA, ultimately leading to cell death. The confluence of DNA repair and cell cycle regulation provides a mechanistic rationale combining azenosertib with TOP1 inhibitors, as well as antibody drug conjugates (ADCs) utilizing these inhibitors as payloads.

Methods

Synergy between azenosertib and TOP1 inhibitors (irinotecan, SN38 and deruxtecan (Dxd)) was evaluated in cell lines across several cancer types. DNA damage and apoptosis were examined by western blot. Anti-tumor effect of azenosertib and TOP1 inhibitors were evaluated in HCC1569 model (HER2⁺ breast cancer) and OV90 model (ovarian cancer). The combination of azenosertib and sacituzumab govitecan (SG) (TROP2 ADC with an SN38 payload) or trastuzumab deruxtecan (T-Dxd) (HER2 ADC with a Dxd payload) were evaluated in MDA-MB-231 or HCC1569 model, respectively.

Results

The combination of azenosertib with TOP1 inhibitors demonstrated significant synergistic effects in all cell lines tested. A significant increase in γH2AX and cleaved caspase-3 was observed in the combination treated cells. The combination of azenosertib with irinotecan enhanced tumor growth inhibition in HCC1569 and OV90 models. Additionally, azenosertib significantly improved the efficacy of SG in the TROP2_low MDA-MB-231 model. Azenosertib in combination with T-Dxd resulted in 50% of animals showing complete tumor regression (CR), compared with no CRs in monotherapy arms in HCC1569 model.

Conclusions

These data suggest that azenosertib significantly improves the anti-tumor effect of TOP1 inhibitors as well as ADCs with TOP1 inhibitor payload. The combination could be a generalizable therapeutic approach for improving responses to ADCs in patients with advanced solid tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Zentalis Pharmaceuticals Inc.

Funding

Has not received any funding.

Disclosure

J. Ma, X. Guo, C. Lee, O. Harismendy, A. Jubb, D. Kim, M.R. Lackner: Financial Interests, Personal, Full or part-time Employment: Zentalis Pharmarceuticals Inc. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, OnCusp Therapeutics, Zymeworks; Financial Interests, Personal, Other, Consulting: Calibr, Ecor1, Exelixis, GT Aperion, Infinity Pharmaceuticals, Loxo-Oncology, LegoChem Bio, Lengo Therapeutics, Tallac Therapeutics, Becton Dickinson, eFFECTOR Therapeutics, Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Incyte, Karyopharm, Protai, TheraTechnologies, Zentalis, FogPharma, Harbinger Health, Mersana Therapeutics, Sanofi Pharmaceuticals; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Invited Speaker: Dava Oncology; Financial Interests, Institutional, Other, Local PI/Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI/Research Grant/Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis, Jazz Pharmaceuticals, Zymeworks; Financial Interests, Institutional, Other, Local PI/Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation, Dava Oncology.