Abstract 2494: ATR inhibitor AZD6738 as monotherapy and in combination with olaparib or chemotherapy: defining pre-clinical dose-schedules and efficacy modelling
Authors: Lau Alan Y. , Yates James , Wilson Zena , Young Lucy A. , Hughes Adina M. , Berges Alienor , Cheung Amy , Odedra Rajesh , Brown Elaine , O'Connor Mark J. , Hollingsworth Simon 
Published: July 2017

Introduction: AZD6738 is a potent and selective oral inhibitor of the ataxia telangiectasia and rad3 related (ATR) protein kinase. ATR has a key role in the DNA replication stress response (RSR) pathway of DNA repairby facilitating the recovery and repair of potentially cytotoxic persistent, stalled DNA replication forks. Inhibition of ATR leads to the inability to resolve replication associated damage and the accumulation of DNA strand breaks, which if remains unrepaired leads to cell death. AZD6738 is currently in Phase I/II clinical trials being evaluated as a monotherapy and in combination with novel agents olaparib / Lynparza (PARP DNA damage response inhibitor), durvalumab (PD-L1 immune checkpoint inhibitor) and DNA-damaging agents such as carboplatin and ionising radiation. Critical in helping to guide the clinical usage of AZD6738 and maximise patient benefit, pre-clinical studies were performed to determine optimal doses and schedules as monotherapy and in combination with olaparib and carboplatin.

Experimental procedures: Human cancer cell lines, xenograft and patient-derived explant (PDX) models of non-small cell lung cancer (NSCLC), head & neck squamous cell carcinoma (HNSCC), and triple-negative breast cancer (TNBC) were tested comparing once daily versus twice daily dosing, the number of consecutive days dosing (3 days/week, 5 days/week, continuous) and co-dosing versus sequential or intermittent dosing with AZD6738 alone or in combination with olaparib or carboplatin. The magnitude and duration of anti-tumour responses were then compared with AZD6738 mouse pharmacokinetic (PK), pharmacodynamic (PD) and in vitro target (IC) / growth inhibition (GI) profiles.

Results: A mathematical model was derived which adequately described the AZD6738 PK/PD-efficacy relationship. This modelling confirms that duration of cover (time) above cellular ATR target inhibition thresholds (IC90 pCHK1 / GI90) per day, rather than Cmax or exposures per se, is the major determinant of anti-tumour responses. As monotherapy, in sensitive ATM-deficient models, it is necessary to inhibit ATR continuously to give tumour stabilisation, which can be achieved through repeat daily of AZD6738 over several weeks. Co-dosing AZD6738 in combination with olaparib or carboplatin gives best efficacy compared to sequential dosing and PK cover over the first 48-72 hours is necessary to give tumour regressions. The models predict that extending the duration of ATR cover, achieved through repeat daily dosing, further increases efficacy. These pre-clinical dose-schedules were compared to human free plasma AZD6738 PK data and predicted efficacious exposures found to be clinically achievable.

Conclusions: Together these data further support the clinical evaluation of AZD6738 and suggest optimal dosing schedules for ATR inhibitors.

Citation Format: Alan Y. Lau, James Yates, Zena Wilson, Lucy A. Young, Adina M. Hughes, Alienor Berges, Amy Cheung, Rajesh Odedra, Elaine Brown, Mark J. O'Connor, Simon Hollingsworth. ATR inhibitor AZD6738 as monotherapy and in combination with olaparib or chemotherapy: defining pre-clinical dose-schedules and efficacy modelling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2494. doi:10.1158/1538-7445.AM2017-2494