Docirbrutinib (AS-1763), a novel non-COVALENT pan-mutant BTK inhibitor, demonstrates durable clinical responses in patients with previously treated B-cell malignancies: Data from an ongoing Phase 1b study

Abstract Background Covalent and non-covalent Bruton's tyrosine kinase inhibitors (c/ncBTKis) are approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and B-cell non-Hodgkin lymphoma (NHL), but their long-term efficacies are limited due to the off-target toxicities and the acquired resistance mutations in BTK such as C481x, T474I and L528W. Docirbrutinib (AS-1763) is a highly selective, pan-mutant ncBTKi, which inhibits both wild-type and various c/ncBTKi-resistant mutations including C481x, T474x and L528x with IC50 values of <10 nM (Kawahata et al. J Med Chem 2021; 64,14129-14141, Timofeeva et al. ASH2024). Docirbrutinib demonstrated strong anti-tumor activities in B-cell lymphoma cell lines harboring resistant BTK mutations including a kinase-dead BTK L528W (unpublished). Here we report the results of docirbrutinib from the ongoing Phase 1b study in B-cell malignancies (NCT05602363). Methods This is a multicenter, open-label, Phase 1b study in patients (pts) with CLL/SLL or B-cell NHL who received ≥2 prior therapies including c/ncBTKis. The study includes 3+3 dose escalation and dose expansion parts. The dose expansion part consists of three cohorts; CLL/SLL pts are allocated to Cohort 1 and NHL pts to Cohort 2, both aimed at determining the recommended Phase 2 dose (RP2D), and CLL/mantle cell lymphoma (MCL) pts previously treated with a ncBTKi, pirtobrutinib, to Cohort 3 for exploratory efficacy evaluation. Each cohort includes 2-3 dose levels. Docirbrutinib was orally administered twice daily (BID). Results As of the 18 July 2025 cutoff date, 31 pts (19 CLL, 1 SLL, 4 follicular lymphoma [FL], 3 MCL, 1 marginal zone lymphoma [MZL], 3 Waldenström macroglobulinemia [WM]) were assigned to 5 dose levels; 100 (n=3), 200 (n=3), 300 (n=18), 400 (n=4), and 500 mg BID (n=3). Median age was 69 years (range, 46-86). The median number of prior lines of therapy for CLL was 4 (range, 2-7) including cBTKi (20/20 [100%]) and venetoclax (13/20 [63%]), and that for NHL was 4 (range, 2-6) including cBTKi (1/4 [25%] FL, 2/3 [67%] MCL, 1/3 [33%] WM) and pirtobrutinib (1/3 [33%] MCL). For 20 CLL/SLL pts, baseline genetic features include IGHV-unmutated (19/19, 100%), del(17p)/TP53 mutated (8/19, 42%), del(11q) (3/18, 17%), and BTK C481S mutation (5/19, 26%). Median treatment duration was 6.0 (range, 0.5-23.6) months. Docirbrutinib was well tolerated across all dose levels in the dose escalation part with no dose-limiting toxicity up to the highest dose level of 500 mg BID, and the maximum tolerated dose was not reached. For the dose expansion part, 300 mg BID was selected as a low dose level in Cohorts 1 and 2 and 400 mg BID in Cohort 3. The dose expansion part is currently ongoing to determine the RP2D. Among all 31 pts, no drug-related atrial fibrillation or hypertension was reported. Drug-related ≥G3 TEAEs reported were neutrophil count decreased in 2 pts, ALT/AST increased in 1 pt, anemia, hematoma and hemorrhagic shock in 1 pt on concomitant anticoagulation. Due to drug-related AEs, 1 pt temporarily experienced dose interruption/reduction (ALT/AST elevation), and 1 pt discontinued the study (hematoma). 24 pts (16 CLL, 3 FL, 2 MCL, 1 MZL, 2 WM) who had at least one response assessment after dosing were considered evaluable for efficacy across all dose levels. Of the 16 efficacy-evaluable CLL pts, 8 pts achieved partial response (PR) or PR with lymphocytosis (overall response rate [ORR] 50%), and 7 pts achieved stable disease with 4 of them remaining on treatment and showing 10.8-49.9% reduction in tumor size, with responses continuing to deepen. The median duration of response of the 8 CLL responders has not been reached, with 2 pts achieving >18 months and 2 pts >12 months. For 8 efficacy-evaluable NHL pts, 2 of 2 MCL pts achieved tumor response (ORR 100%, 1 complete response and 1 PR) and 1 of 2 WM pts achieved PR (ORR 50%,1 PR and 1 minor response). All MCL and WM pts enrolled are still on treatment. Summary/Conclusion In the ongoing Phase 1b study, docirbrutinib demonstrated encouraging anti-tumor activity with a favorable safety profile and durable responses in CLL pts heavily treated with prior therapies including cBTKi and venetoclax and promising responses in MCL and WM pts. Updated data will be presented at the annual meeting.