Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation
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
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
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Clinical Research and Public Health Oncology

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

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

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Figure 3

Antitumor responses.

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Antitumor responses. (A) Waterfall plot of best change in sum of longest...
(A) Waterfall plot of best change in sum of longest diameters of target lesions (SLD), with corresponding duration on study. (B) Swimmer plot of evaluable patients. (C) Spider plot of evaluable patients. (D–I) Representative scans from responding patients. (D) Ovarian clear cell carcinoma, ARID1A loss, RECIST PR, 1,763 days on study, 160 mg BD, intermittent. (E) HNSCC, MRE11, and CDKN2A mutation, 1,194 days on study. (F) Esophageal squamous cell carcinoma, HR and Fanconi pathway deficiency, RECIST PR, 575 days on study, 160 mg BD intermittent. (G) Nasopharyngeal carcinoma, NRAS activation, RECIST PR, 341 days on study, 240 mg BD. (H) HNSCC, RECIST PR, 106 days on study, 40 mg BD. (I) Pancreatic adenocarcinoma, no clear mutation, unconfirmed PR, 480 days on study, 160 mg BD intermittent. Tumor protein profiling: IHC tumor staining was performed on the cases mentioned. Arrows indicate responding tumor lesions. (J) Clear cell ovarian carcinoma with loss of ARID1A, H score 0. Red arrowhead indicates tumor cells; white indicates stroma. (K) Eccrine adenocarcinoma with loss of ARID1A, H score 0. (L) Lung adenocarcinoma, ARID1A mutation but no protein loss. H score 290. (M) Cervix adenocarcinoma, ARID1A mutation but no protein loss. H score 300. (N) Clear cell ovarian carcinoma, ARID1A mutation but no protein loss. H score 235. (O) Serous ovarian carcinoma, ATM protein loss. (P) Same tumor as in M, showing cyclin E1 overexpression. H score 169. (Q) Peritoneal carcinoma, CCNE1 amplification on sequencing, cyclin E1. H score 210. (R) Serous endometrial carcinoma, CCNE1 amplification on sequencing, cyclin E1. H score 224. (S) Serous endometrial carcinoma, CCNE1 overexpression by IHC, cyclin E1. H score 155.