Paper Details

ABSTRACT

Background:

Docirbrutinib (AS-1763) is a highly selective, pan-mutant non-covalent BTK inhibitor (ncBTKi), which inhibits both wild-type and various c/ncBTKi-resistant mutations including C481x, T474x and L528x with IC₅₀ values of <10 nM and shows strong anti-tumor activity in B-cell lymphoma cell lines harboring resistant BTK mutations including a kinase-dead BTK L528W. We report updated efficacy and safety data for docirbrutinib in patients (pts) with CLL/SLL, along with pharmacokinetic (PK) data from the ongoing Phase 1b study of docirbrutinib in B-cell malignancies (NCT05602363).

 Methods:

This is a multicenter, open-label, Phase 1b study in pts with CLL/SLL or B-cell non-Hodgkin lymphoma (NHL) who had received ≥2 prior therapies including c/ncBTKis. The study includes dose-escalation and dose-expansion parts. The dose expansion part includes three cohorts: CLL/SLL (Cohort 1) and NHL (Cohort 2) for determination of the recommended Phase 2 dose (RP2D), and pirtobrutinib (ncBTKi)-pretreated CLL/SLL and mantle cell lymphoma (MCL) (Cohort 3) for exploratory efficacy evaluation. Docirbrutinib was administered orally at doses ranging from 100-500 mg twice daily (BID). Safety and efficacy are presented for pts with CLL/SLL across all dose levels and at the provisional RP2D of 400 mg BID. PK analyses were performed in all evaluable pts enrolled in the study. Tumor response was assessed by investigators per iwCLL2018 for CLL and Lugano for SLL.

 Results:

As of 10 July 2026, 33 pts with CLL/SLL received five dose levels: 100 (n=3), 200 (n=2), 300 (n=12), 400 (n=15), and 500 mg BID (n=1). Median age was 69 years (range, 56-86). The median number of prior lines of therapy was 4 (range, 2-13), including cBTKi (33/33, 100%), BCL2i (21/33, 64%), and pirtobrutinib (3/33, 9%). Baseline genetic features included IGHV-unmutated (30/31, 97%), del(17p)/TP53-mutated (12/32, 38%), del(11q) (5/30, 17%), BTK C481x (11/28, 39%), BTK A428D (2/28, 7%), BTK L528W (3/28, 11%), and PLCG2 mutations (2/28, 7%). Median duration of treatment was 9.8 months (range, 0.6-35.3). The most common treatment-emergent adverse events (TEAEs, ≥20%) were diarrhea (27%; no Grade [G] ≥3), nausea (24%; no ≥G3), and upper respiratory tract infection (21%; no ≥G3). No drug-related atrial fibrillation or hypertension was reported. Drug-related ≥G3 TEAEs were reported in 5 pts (15%): neutrophil count decreased or neutropenia in 3 pts (9%), hematuria in 1 pt (3%), hematoma on concomitant anticoagulation and subsequent anemia and hemorrhagic shock in 1 pt (3%), and hypokalemia in 1 pt (3%). Due to drug-related AEs, 1 pt (3%) experienced dose interruption (G3 hypokalemia), and 1 pt (3%) discontinued treatment (G4 hematoma). The frequency and severity of adverse events at 400 mg BID (provisional RP2D) were not notably higher than those observed across all dose levels.

Among 28 efficacy-evaluable pts with no prior exposure to ncBTKi, the overall response rate (ORR, partial response with lymphocytosis [PR-L] or better) was 57% (16/28) across all dose levels. After a median follow-up of 12.5 months (range, 0.6-35.3), the median progression-free survival (PFS) has not yet been reached, with 4 pts remaining progression-free beyond 24 months. The median duration of response has not yet been reached. In pts allocated to 400 mg BID, the ORR was 73% (8/11). Among them, 6 of 7 pts double-exposed to cBTKi and BCL2i achieved PR or PR-L (ORR 86%), and 3 of 4 pts harboring BTK C481x mutations achieved PR (ORR 75%), including 1 pt with both BTK C481S and L528W mutations and 1 pt with both BTK C481S and PLCG2 mutations.

In Cohort 3, 3 pts with CLL were enrolled, all of whom had previously been triple-exposed to cBTKi, ncBTKi and BCL2i. 2 pts had stable disease, including 1 pt with SD lasting >6 months, and 1 pt experienced disease progression. Given the limited sample size and immature data, efficacy remains under evaluation in this Cohort.

PK analyses showed a dose-dependent increase in exposure up to 400 mg BID. At steady state (Day 8), >80% of pts treated with 400 mg BID achieved trough concentrations above the BTK IC₉₀, indicating sustained target inhibition throughout the dosing interval.

Conclusion:

Docirbrutinib demonstrated a favorable safety profile and robust efficacy in pts with CLL/SLL including those previously double-exposed to cBTKi and BCL2i. These results support the continued clinical development of docirbrutinib for relapsed/refractory CLL.