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Twice-Daily Dosing of Acalabrutinib Well-Tolerated, Effective for BTK Inhibition in CLL
In a phase 2 study of patients with relapsed or refractory and high-risk, treatment-naïve chronic lymphocytic leukemia (CLL), acalabrutinib was shown to be clinically effective, with twice daily dosing maintaining near-complete occupancy of BTK in blood and tissues than once daily dosing (Blood. 2020 Jul 2;136[1]:93-105).
“Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors,” wrote lead investigator Clare Sun, MD, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, and colleagues.
“However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined,” they continued.
Thus, Dr Sun et al randomized a cohort of 48 patients with relapsed/refractory or high-risk, treatment-naïve CLL to receive acalabrutinib 100 mg twice daily or 200 mg once daily in an effort to evaluate the safety, efficacy, and pharmacodynamics of the therapy.
Acalabrutinib therapy was demonstrated to be well-tolerated. Twice-daily dosing yielded an overall response rate (ORR) of partial response or better in 95.8% (95% CI, 78.9-99.9) of patients and an estimated 24-month progression-free survival (PFS) rate of 91.5% (95% CI, 70.0-97.8). Once-daily dosing yielded an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated 24-month PFS rate of 87.2% (95% CI, 57.2-96.7).
Of note, BTK resynthesis occurred more rapidly in patients with CLL versus in healthy volunteers, and twice-daily dosing maintained higher BTK occupancy and achieved more potent pathway inhibition than once-daily dosing.
“Small increments in occupancy attained by BID [twice daily] dosing relative to QD [once daily] dosing compounded over time to augment downstream biological effects,” Dr Sun and colleagues said.
“The impact of BTK occupancy on long-term clinical outcomes remains to be determined,” they concluded.—Hina M. Porcelli
