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

doi:10.1172/JCI175369

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 KwatraLorna 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

^*Corresponding author for this work

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

BACKGROUND. Phase 1 study of ATR inhibition 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.

Original language	English
Article number	e175369
Journal	Journal of Clinical Investigation
Volume	134
Issue number	2
DOIs	https://doi.org/10.1172/JCI175369
Publication status	Published - 16 Jan 2024

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10.1172/JCI175369

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Dillon, M. T., Guevara, J., Mohammed, K., Patin, E. C., Smith, S. A., Dean, E., Jones, G. N., Willis, S. E., Petrone, M., Silva, C., Thway, K., Bunce, C., Roxanis, I., Nenclares, P., Wilkins, A., McLaughlin, M., Jayme-Laiche, A., Benafif, S., Nintos, G., ... Harrington, K. J. (2024). Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. Journal of Clinical Investigation, 134(2), Article e175369. https://doi.org/10.1172/JCI175369

@article{40c5df2ddc6c400fa337ce3034c39e0f,

title = "Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation",

abstract = "BACKGROUND. Phase 1 study of ATR inhibition 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.",

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

note = "Publisher Copyright: {\textcopyright} 2024, Dillon et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2024",

month = jan,

day = "16",

doi = "10.1172/JCI175369",

language = "English",

volume = "134",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

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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, D, Proszek, P, Martin, P, Moore, L, Swales, KE, Banerji, U, Saunders, MP, Spicer, J, Forster, MD & Harrington, KJ 2024, 'Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation', Journal of Clinical Investigation, vol. 134, no. 2, e175369. https://doi.org/10.1172/JCI175369

TY - JOUR

T1 - Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation

AU - Dillon, Magnus T.

AU - Guevara, Jeane

AU - Mohammed, Kabir

AU - Patin, Emmanuel C.

AU - Smith, Simon A.

AU - Dean, Emma

AU - Jones, Gemma N.

AU - Willis, Sophie E.

AU - Petrone, Marcella

AU - Silva, Carlos

AU - Thway, Khin

AU - Bunce, Catey

AU - Roxanis, Ioannis

AU - Nenclares, Pablo

AU - Wilkins, Anna

AU - McLaughlin, Martin

AU - Jayme-Laiche, Adoracion

AU - Benafif, Sarah

AU - Nintos, Georgios

AU - Kwatra, Vineet

AU - Grove, Lorna

AU - Mansfield, David

AU - Proszek, Paula

AU - Martin, Philip

AU - Moore, Luiza

AU - Swales, Karen E.

AU - Banerji, Udai

AU - Saunders, Mark P.

AU - Spicer, James

AU - Forster, Martin D.

AU - Harrington, Kevin J.

PY - 2024/1/16

Y1 - 2024/1/16

N2 - BACKGROUND. Phase 1 study of ATR inhibition 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.

AB - BACKGROUND. Phase 1 study of ATR inhibition 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.

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U2 - 10.1172/JCI175369

DO - 10.1172/JCI175369

M3 - Article

C2 - 37934611

AN - SCOPUS:85182594738

SN - 0021-9738

VL - 134

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 2

M1 - e175369

ER -

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

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