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

• Published in: The Journal of clinical investigation 2024-01, Vol.134 (2), p.1-14
• Main Authors: Dillon, Magnus T, Guevara, Jeane, Mohammed, Kabir, Patin, Emmanuel C, Smith, Simon A, Dean, Emma, Jones, Gemma N, Willis, Sophie E, Petrone, Marcella, Silva, Carlos, Thway, Khin, Bunce, Catey, Roxanis, Ioannis, Nenclares, Pablo, Wilkins, Anna, McLaughlin, Martin, Jayme-Laiche, Adoracion, Benafif, Sarah, Nintos, Georgios, Kwatra, Vineet, Grove, Lorna, Mansfield, David, Proszek, Paula, Martin, Philip, Moore, Luiza, Swales, Karen E, Banerji, Udai, Saunders, Mark P, Spicer, James, Forster, Martin D, Harrington, Kevin J
• Format: Article
• Language: English
• Subjects: Antitumor activity; Ataxia; Ataxia telangiectasia; Ataxia Telangiectasia Mutated Proteins - genetics; Biopsy; Bone marrow; Cancer; Clinical Medicine; DNA damage; DNA repair; Dosage; Drug dosages; Drug therapy; Epistaxis; Genetic aspects; Genomics; Hematology; Humans; Indoles; Inflammation; Inflammation - drug therapy; Kinases; Leukopenia; Medical research; Medicine, Experimental; Morpholines; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Patients; Pharmaceutical industry; Pharmacodynamics; Pharmacokinetics; Pyrimidines; Radiation therapy; Radiotherapy; Solid tumors; Sulfonamides; Thrombocytopenia; Toxicity; Tumors
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI175369

BACKGROUNDPhase 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.METHODSThe 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).RESULTSIntermittent 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.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.