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

Abstract

BACKGROUND: PATRIOT was the first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors. METHODS: Primary objective was safety. Secondary objectives included assessment of anti-tumor responses, pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received ceralasertib 20-240 mg 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 (PR, 40-240 mg BD), 34 (52%) stable disease (SD) including 1 unconfirmed partial response, 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 non-responding. CONCLUSION: Ceralasertib monotherapy was tolerated at 160 mg BD intermittent and associated with anti-tumor activity. 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. FUNDING: AstraZeneca provided funding for components of the clinical conduct of PATRIOT and drug supply and labelling.