Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation

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Abstract

BACKGROUND Phase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODS The primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20–240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTS Intermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40–240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage–response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSION Ceralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATION Clinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDING Cancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.

Authors

Magnus T. Dillon, Jeane Guevara, Kabir Mohammed, Emmanuel C. Patin, Simon A. Smith, Emma Dean, Gemma N. Jones, Sophie E. Willis, Marcella Petrone, Carlos Silva, Khin Thway, Catey Bunce, Ioannis Roxanis, Pablo Nenclares, Anna Wilkins, Martin McLaughlin, Adoracion Jayme-Laiche, Sarah Benafif, Georgios Nintos, Vineet Kwatra, Lorna Grove, David Mansfield, Paula Proszek, Philip Martin, Luiza Moore, Karen E. Swales, Udai Banerji, Mark P. Saunders, James Spicer, Martin D. Forster, Kevin J. Harrington