Phase 2 study of DZD8586, a non-covalent BBB penetrant LYN/BTK dual inhibitor, as monotherapy in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL; TAI-SHAN9).

Abstract

e19050 Background: Diffuse large B-cell lymphoma (DLBCL) is a phenotypically and genetically heterogeneous disease with unmet medical needs. The therapeutic efficacy of Bruton's tyrosine kinase (BTK) inhibitors in DLBCL remains suboptimal, partly due to activation of the phosphatidylinositol 3-kinase (PI3K) pathway, which undermines BTK inhibitor performance. DZD8586 is designed as a LYN/BTK dual inhibitor with full blood-brain barrier (BBB) penetration and high selectivity against other TEC family kinases. Preclinical evidence showed that this dual-targeting approach significantly improved DZD8586’s antitumor efficacies in a range of tumor models over BTK only inhibitors. Here we report preliminary result from the ongoing phase 2 study of DZD8586 monotherapy in patients with r/r DLBCL (TAI-SHAN9; NCT06539195). Methods: Adult patients (≥18 years) with histologically confirmed DLBCL, refractory or relapse after standard treatment, and ineligible or unwilling for transplantation were enrolled. DZD8586 was administered orally as monotherapy until disease progression, unacceptable toxicity, or withdrawal. Anti-tumor efficacy was assessed by investigators according to Lugano 2014 criteria. Adverse events were graded per CTCAE v5.0. Results: As of January 8, 2025, 39 patients received DZD8586 at 25 mg (n=4), 50 mg (n=18), and 75 mg (n=17) once daily; 19 (49%) remained on treatment. Median age was 59 years, 21 (53.8%) were male, 26 (66.7%) had an ECOG PS of 1, and 16 (41%) had intermediate to high-risk disease per International Prognostic Index (IPI). Six (15.4%) and 32 (82.1%) patients had molecular subtypes of GCB and non-GCB DLBCL. Patients received 1-4 prior lines of therapy, and all were treated with anthracycline-and CD20-antibody based chemoimmunotherapy. Among 25 efficacy evaluable patients, 10 achieved tumor response, with objective response rate (ORR) of 42.9% at 50 mg and 50% at 75 mg, respectively, and complete response rates (CRR) of 28.6% and 50% at these two dose levels. Tumor responses were observed in both GCB and non-GCB subtypes. The longest PFS was 5.6 months (treatment ongoing). Most treatment emergent adverse events (TEAEs) were mild or moderate. Grade 3/4 drug related TEAEs reported in ≥2 patients included thrombocytopenia (7.7%), neutropenia (5.1%), and upper respiratory tract infection (5.1%). No bleeding or atrial fibrillation was reported. No TEAE led to death or drug discontinuation. Conclusions: DZD8586 showed promising anti-tumor activity and a manageable safety profile in patients with r/r DLBCL. Updated data will be presented at the meeting. Clinical trial information: NCT06539195 .