Preliminary Results from a Phase 1b Study of Non-Covalent Pan-Mutant BTK Inhibitor Docirbrutinib (AS-1763) in Patients with Previously Treated B-Cell Malignancies

Background: Covalent Bruton’s tyrosine kinase inhibitors (cBTKis) are approved for the treatment of B-cell malignancies, but their long-term efficacies are limited due to the off-target toxicities and the acquired resistance mutations in BTK such as C481x. A non-covalent BTKi (ncBTKi), pirtobrutinib, was recently approved for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) after at least 2 lines of systemic therapies including cBTKis, but acquired resistance via BTK T474I and L528W mutations has been reported.

Docirbrutinib (AS-1763) is a highly selective ncBTKi which inhibits both wild-type and various c/ncBTKi-resistant mutations including C481x, T474x and L528x (pan-mutant BTKi) with IC₅₀ values of <10 nM in in vitro assays and demonstrated strong anti-tumor activities in cellular and animal studies (Kawahata et al. J Med Chem 2021; 64,14129-14141, Tantawy et al. ASH2023). Here we report the preliminary results of docirbrutinib monotherapy 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 B-cell malignancies who received ≥2 prior therapies, including cBTKis. Recently, the clinical protocol was amended to allow pts with prior ncBTKi. The study has 2 parts: 3+3 dose escalation and dose expansion. Docirbrutinib oral tablets were administered twice daily (BID). Dose-limiting toxicities (DLTs) were assessed during the first cycle (28 days).

Results: As of 19 July 2024, 14 pts (9 CLL, 3 follicular lymphoma [FL], 1 MCL, 1 marginal zone lymphoma [MZL]) were enrolled to 5 dose levels in the dose escalation part: 100 mg BID (n=3; 3 CLL), 200 mg BID (n=3; 2 CLL, 1 FL), 300 mg BID (n=3; 2 CLL, 1 FL), 400 mg BID (n=3; 2 CLL, 1 MCL) and 500 mg BID (n=2; 1 FL, 1 MZL). Median age was 67 years (range, 46-77). Median lines of prior therapies were 4 (range, 2-5), including chemotherapy + anti-CD20 antibody (all pts [100%]), cBTKi (9/9 CLL [100%], 1/2 FL [50%]), and venetoclax (6/9 CLL [67%]). For the 9 pts with CLL, baseline genetic features include IgHV unmutated (9/9, 100%), deletion 17p (3/9, 33%), TP53 mutation (4/8, 50%), and BTK C481S (2/8, 25%). No DLTs were observed at doses up to 500 mg BID, and the maximum tolerated dose has not been reached yet. To date, among all 14 pts, no drug-related atrial fibrillation or bleeding was reported; neutropenia (2/14, 14%) and ALT/AST elevations (1/14, 7%) were the only drug-related ≥G3 adverse events (AEs). 1 pt experienced dose interruption due to asymptomatic liver enzyme elevations (G3). No treatment discontinuation due to drug-related AE occurred. Among 9 pts with CLL, 5 pts achieved partial response (PR) or PR with lymphocytosis (PR-L) and 3 pts showed stable disease (SD) with 16-45% reduction in tumor size. Among 3 efficacy-evaluable pts with NHL (2 FL and 1 MCL), 2 pts (1 FL, 1 MCL) showed SD. 2 pts with FL and MZL at 500 mg BID are awaiting the initial radiologic assessment at the end of Cycle 2. Currently available pharmacokinetic data up to 500 mg BID indicated the increase in exposures with doses, and the exposure exceeded the calculated IC₉₀ for BTK at doses ≥300 mg BID throughout the dosing interval. Among 4 pts with CLL receiving ≥300 mg BID, 3 of 4 pts (75%) achieved PR or PR-L, and 1 pt showed SD with 45% tumor reduction. 11 of 15 pts continue on the study treatment with a median treatment duration of 4.9 months.

Conclusion: The preliminary safety and efficacy data from the ongoing study of docirbrutinib in heavily pretreated pts with B-cell malignancies are encouraging. We plan to move forward to the expansion part to determine recommended phase 2 dose. Updated data will be presented at the annual meeting.