Ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib dose optimization in patients with biomarker-selected advanced solid tumors (TRESR study).

Autor:	Fontana E; Sarah Cannon Research Institute UK, London, UK., Rosen E; Early Drug Development and Breast Medicine Services, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Lee EK; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Højgaard M; Department of Oncology, Rigshospitalet, Copenhagen, Denmark., Mettu NB; Medical Oncology, Duke University, Durham, NC, USA., Lheureux S; Princess Margaret Cancer Centre, Toronto, ON, Canada., Carneiro BA; Legorreta Cancer Center at Brown University and Lifespan Cancer Institute, Division of Hematology/Oncology, Department of Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA., Cote GM; Mass General Cancer Center, Boston, MA, USA., Carter L; Division of Cancer Sciences, The University of Manchester, Manchester, UK.; The Christie NHS Foundation Trust, Manchester, UK., Plummer R; Sir Bobby Robson Cancer Trials Research Centre, Freeman Hospital, Newcastle upon Tyne, UK., Mahalingam D; Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Fretland AJ; Repare Therapeutics, Cambridge, MA, USA., Schonhoft JD; Repare Therapeutics, Cambridge, MA, USA., Silverman IM; Repare Therapeutics, Cambridge, MA, USA., Wainszelbaum M; Repare Therapeutics, Cambridge, MA, USA., Xu Y; Repare Therapeutics, Cambridge, MA, USA., Ulanet D; Repare Therapeutics, Cambridge, MA, USA., Koehler M; Repare Therapeutics, Cambridge, MA, USA., Yap TA; Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jazyk:	angličtina
Zdroj:	Journal of the National Cancer Institute [J Natl Cancer Inst] 2024 Sep 01; Vol. 116 (9), pp. 1439-1449.
DOI:	10.1093/jnci/djae098
Abstrakt:	Background: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects. Methods: Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on, 1 week off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating tumor DNA (ctDNA)-based molecular response rate. Results: The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (hazard ratio = 0.23, 2-sided P = .02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity. Conclusion: The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering a substantial reduction in the incidence of anemia without any compromise to efficacy. Clinical Trial Id: NCT04497116. (© The Author(s) 2024. Published by Oxford University Press.)
Databáze:	MEDLINE
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