Abstract 2269: ATR inhibitor M6620 enhances anti-tumor efficacy of the combination of the anti-PD-L1 antibody avelumab with platinum-based chemotherapy
Authors: Alimzhanov Marat , Soulard Patricia , Zimmermann Astrid , Schroeder Andreas , Mehr Keyvan Tadjalli , Amendt Christiane , Sim Geok Choo , Blaukat Andree , Halle Joern-Peter , Zenke Frank T. 
Published: August 2019

Recently, combination of checkpoint inhibitors with chemotherapy demonstrated significant improvement of overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone in patients with metastatic non-squamous and squamous non-small cell lung cancer (NSCLC). However still a larger number of patients do not benefit of the combination treatment. Ataxia telangiectasia mutated and Rad3 related kinase (ATR) is one of the key players in the DNA damage response (DDR) to replication stress. M6620 is a potent and selective ATR inhibitor currently in Phase I clinical studies in combination with multiple DNA-damaging drugs. M6620 has been shown to sensitize cancer cells to the lethal effects of DNA-damaging chemotherapeutic agents. Here we tested the hypothesis that ATR inhibitor M6620 could further enhance anti-tumor efficacy of chemotherapy combinations with avelumab, an FDA approved human IgG1 anti-PD-L1 monoclonal antibody, in vivo.

We profiled a panel of murine tumor cell lines to identify models sensitive to combination treatment of M6620 with cisplatin, carboplatin or oxaliplatin. Addition of M6620 to the chemotherapeutic agents in vitro potentiated growth inhibition effect and led to the increase in markers of immunogenic cell death (ICD) in the sensitive tumor cell lines. Based on these data we investigated anti-tumor efficacy of carboplatin or cisplatin in combination with M6620 and avelumab in MC38 murine colorectal tumor model. The triple combination regimens demonstrated a statistically significant better control of tumor growth, more frequent tumor regressions and increased overall survival compared to the double combination treatment groups. The triplet combination regimens were well tolerated as assessed by changes in body weight and clinical signs. Animals with complete tumor responses were re-challenged with MC38 tumor cells and were found refractory to the second tumor inoculation, indicating that durable, protective anti-tumor immunity was established in complete responders.

Taken together, robust anti-tumor efficacy and acceptable toxicity of selected triplet combinations in preclinical models provide strong rationale for combining avelumab with M6620 and carboplatin in patients with PARP inhibitor resistant recurrent ovarian cancer.

Citation Format: Marat Alimzhanov, Patricia Soulard, Astrid Zimmermann, Andreas Schroeder, Keyvan Tadjalli Mehr, Christiane Amendt, Geok Choo Sim, Andree Blaukat, Joern-Peter Halle, Frank T. Zenke. ATR inhibitor M6620 enhances anti-tumor efficacy of the combination of the anti-PD-L1 antibody avelumab with platinum-based chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2269.