Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation
Magnus T. Dillon, … , Martin D. Forster, Kevin J. Harrington
Magnus T. Dillon, … , Martin D. Forster, Kevin J. Harrington
Published November 7, 2023
Citation Information: J Clin Invest. 2024;134(2):e175369. https://doi.org/10.1172/JCI175369.
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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 4

Immune profiling.

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Immune profiling. (A) H&E and PD-L1 IHC staining of paired biopsies ...
(A) H&E and PD-L1 IHC staining of paired biopsies of a responding patient (HNSCC, 40 mg, RECIST PR), showing infiltration of PD-L1–positive immune cells after 2 weeks of ceralasertib. Scale bar: 200 mm. (B) Fold change (FC) in percentage of CD45+ cells in peripheral blood after 2 weeks of ceralasertib (day 14) and after a 2-week break (day 29) compared with baseline sample for the indicated cell type. Median and IQR indicated. Statistical significance by Wilcoxon’s test. (C) Shown is log2 fold change in percentages of the CD8+ T, CD4+ T, and unconventional (Unconv) T cells of the following populations: TN (T naive as CCR7+CD45RA+), TCM (T central memory as CCR7+CD45RA–), TEM (T effector memory as CCR7–CD45RA–), and TEMRA (T effector memory RA as CCR7–CD45RA+) from baseline, median, and IQR indicated. (D) Fold change in percentage of CD45 of memory CD4-TEMRA (effector memory reexpressing CD45RA) from baseline. Median and IQR indicated. Statistical significance by Wilcoxon’s test. (E) Fold change in percentage of NK cells or CD8+ T cells in the peripheral blood of (from left to right) NK cell NKG2A-positive, NK cell CD69-positive and CD8+ T cell PD-1–positive from baseline. Median and IQR indicated. Statistical significance by Wilcoxon’s test. (F) Left: fold change in percentage of CD45 of classical monocytes, as above. Middle: change in gMDSC as a percentage of CD45-positive cells, right: change in mMDSC as a percentage of CD45-positive cells. Median and IQR indicated. *P < 0.05, unpaired t test. (G) Fold change versus baseline in levels of the indicated plasma cytokines after 2 weeks of ceralasertib. *P < 0.05, paired t test.