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Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation
Dillon, MT Guevara, J Mohammed, K Patin, EC Smith, SA Dean, E Jones, GN Willis, SE Petrone, M Silva, C
Dillon, MT
Guevara, J
Mohammed, K
Patin, EC
Smith, SA
Dean, E
Jones, GN
Willis, SE
Petrone, M
Silva, C
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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.
Authors
Dillon, MT
Guevara, J
Mohammed, K
Patin, EC
Smith, SA
Dean, E
Jones, GN
Willis, SE
Petrone, M
Silva, C
Thway, K
Bunce, C
Roxanis, I
Nenclares, P
Wilkins, A
McLaughlin, M
Jayme-Laiche, A
Benafif, S
Nintos, G
Kwatra, V
Grove, L
Mansfield, DC
Proszek, P
Martin, P
Moore, L
Swales, KE
Banerji, U
Saunders, Mark P
Spicer, J
Forster, MD
Harrington, KJ
Guevara, J
Mohammed, K
Patin, EC
Smith, SA
Dean, E
Jones, GN
Willis, SE
Petrone, M
Silva, C
Thway, K
Bunce, C
Roxanis, I
Nenclares, P
Wilkins, A
McLaughlin, M
Jayme-Laiche, A
Benafif, S
Nintos, G
Kwatra, V
Grove, L
Mansfield, DC
Proszek, P
Martin, P
Moore, L
Swales, KE
Banerji, U
Saunders, Mark P
Spicer, J
Forster, MD
Harrington, KJ
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Date
2023
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Article
Citation
Dillon MT, Guevara J, Mohammed K, Patin EC, Smith SA, Dean E, et al. Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. The Journal of clinical investigation. 2023 Nov 7. PubMed PMID: 37934611. Epub 2023/11/07. eng.