Dose and BTK occupancy relationship in the prospective Phase 2 TAILOR study: Exploratory end point analysis of the ibrutinib monotherapy cohorts in patients with previously untreated chronic lymphocytic leukemia

Abstract Introduction Continuous treatment with a Bruton's tyrosine kinase inhibitor (BTKi) is a standard of care option for patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). Ibrutinib (Ibr), the first-in-class BTKi, has demonstrated survival benefits comparable to an age-matched general population. In the RESONATE-2 trial with up to 10 years of follow-up, Ibr achieved sustained progression-free survival benefit. Furthermore, Ibr dose modifications improved or resolved adverse events (AEs) in ≥ 85% of pts in this study. In the real-world settings, Ibr dose modification approaches may enhance overall tolerability and decrease side effects without impacting efficacy. Previous research has shown that total BTK protein levels decrease during Ibr treatment, and a model-based approach demonstrated that reducing the dose of Ibr to 280 mg following an initial 28-day cycle at 420 mg can effectively sustain BTK inhibition (Ouerdani A et al, 2025). Supporting this, pilot clinical data with limited follow-up have shown that the biological activity of Ibr can be retained following a similar dose modification approach (Chen LS et al, 2018). Here we present the exploratory analyses of the pharmacokinetics and pharmacodynamics data from the randomized Ibr monotherapy cohorts of the prospective phase 2 trial TAILOR study in pts with previously untreated CLL. Methods In the phase 2 TAILOR (NCT05963074) study, pts with untreated CLL received either Ibr + venetoclax or Ibr monotherapy at physician's choice. Ibr monotherapy cohorts were randomized 1:1 to receive Ibr 420 mg once daily (QD) (Cohort 2a) or 1 cycle of Ibr 420 mg QD followed by Ibr 280 mg QD (Cohort 2b) until progression or intolerability. Blood samples from pts receiving Ibr monotherapy were collected at screening, Cycle 1 Day 14 (C1D14), and Cycle 4 Day 1 (C4D1) to assess predose BTK occupancy, and at C1D14/C4D1 to assess plasma Ibr concentration before and after dose administration (at predose, 2 hours [h], and 4h after dosing). Results were summarized using descriptive statistics; Ibr plasma concentrations were calculated as geometric means (gmeans) and BTK occupancy as median of data from the specified cohort/timepoint. Results Blood samples were evaluated from 21 pts: 10 from Cohort 2a and 11 from Cohort 2b. Pts had a median age of 76 years (range, 59-84) and 85.7% were aged ≥ 65 years. Of 21 pts, 7 had a TP53/del(17p) aberration and 14 of 18 assessed pts had unmutated IGHV. Data from additional patient samples will be included in the presentation. In Cohort 2a, predose gmean Ibr plasma concentration was similar at C4D1 compared with C1D14 (2.2 [standard deviation (SD): 1.8] and 2.1 [SD: 2.4] ng/mL) but was higher 2h post treatment at C4D1 compared with C1D14 (58.8 [SD: 42.2] and 32.1 [SD: 48.6] ng/mL), likely due to variability and possibly some slight accumulation of plasma Ibr. In Cohort 2b (proactively dose-reduced cohort), the gmean Ibr plasma concentration was lower at C4D1 compared with C1D14 at predose (1.7 [SD: 3.1] and 3.4 [SD: 14.1] ng/mL) and 2h post treatment (19.2 [SD: 46.2] and 34.0 [SD: 242.7] ng/mL). When comparing gmean Ibr plasma concentration at C4D1 between Cohorts 2a and 2b, the predose and 2h post treatment plasma concentrations were lower for Cohort 2b: 2.2 (SD: 1.8) versus 1.7 (SD: 3.1) ng/mL and 58.8 (SD: 42.2) versus 19.2 (SD: 46.2) ng/mL, respectively. Median predose BTK occupancy was similar between Cohorts 2a and 2b at C1D14 (99.4% [range, 98.7-99.9%] and 98.9% [range, 92.9-100.0%]), and C4D1 (99.5% [range, 98.3-100%] and 99.5% [range, 98.7-100.0%]). Median BTK occupancy for C1D14 and C4D1 combined was 99.4% for Cohort 2a and 99.2% for Cohort 2b. BTK occupancy was observed to be nearly complete for all Ibr plasma concentration levels measured at C1D14 and C4D1. Conclusions In this exploratory end point analysis of the prospective phase 2 TAILOR study, both study cohorts had > 99% median post-baseline BTK occupancy regardless of Ibr dosage group. These results indicate that high BTK occupancy levels can be maintained after proactively reducing Ibr dose to 280 mg QD after 1 cycle with 420 mg QD, with concomitant lower serum Ibr concentration in pts randomized to the proactively dose reduced Cohort 2b. Further analyses are needed to determine whether the observed BTK occupancy and lower Ibr serum concentrations are associated with similar efficacy and better safety outcomes.