Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib.
Blood
; 136(1): 93-105, 2020 07 02.
Article
en En
| MEDLINE
| ID: mdl-32202637
ABSTRACT
Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829.
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1
Banco de datos:
MEDLINE
Asunto principal:
Pirazinas
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Benzamidas
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Leucemia Linfocítica Crónica de Células B
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Inhibidores de Proteínas Quinasas
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Agammaglobulinemia Tirosina Quinasa
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Proteínas de Neoplasias
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Antineoplásicos
Tipo de estudio:
Clinical_trials
Límite:
Aged80
Idioma:
En
Año:
2020
Tipo del documento:
Article