Evaluation of AZD0486, a Novel CD19xCD3 T-Cell Engager, in Relapsed/Refractory Diffuse Large B-Cell Lymphoma in an Ongoing First-in-Human Phase 1 Study: High Complete Responses Seen in CAR-T-Naive and CAR-T-Exposed Patients
Authors: Gaballa Sameh , Hou Jing-Zhou , Devata Sumana , Cho Seok-Goo , Nair Ranjit , Yoon Dok Hyun , Jacobs Ryan , Izutsu Koji , Stevens Don A. , Maruyama Dai , Tam Constantine S. , Sawalha Yazeed , Ramakrishnan Aravind , Matasar Matthew , Brennan Denise , Zhu Sue , Lesley Robin , Oki Yasuhiro , Sermer David , Kim Tae Min 
Published: December 2024

Introduction: AZD0486, a novel IgG4 fully human CD19xCD3 bispecific T-cell engager (TCE), is uniquely designed to bind CD3 with low affinity to reduce cytokine release upon T-cell activation, while preserving effective T-cell cytotoxicity against malignant B cells. AZD0486 was active and well tolerated in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL), including those with R/R diffuse large B-cell lymphoma (DLBCL) (Gaballa, et al. Blood. 2023). Here, we present interim results from the ongoing phase 1, dose-escalation trial of AZD0486 in pts with R/R DLBCL (NCT04594642).
Methods: Pts with R/R CD19+ B-NHL that was R/R to ≥2 prior lines of therapy were eligible. Escalating doses of AZD0486 were administered in either fixed target dose (day [D]1, D15 0.03-2.4 mg), single step-up dose (1SUD) (D1 0.27-1 mg, D15 0.8-10 mg), or double SUD (2SUD) (D1 0.27 mg, D8 1 mg, D15 2.4-15 mg) schedules. AZD0486 was given intravenously every 2 weeks in 28-D cycles (C) for up to 2 years (y). Pts in complete response (CR) after C6 were considered for monthly dosing. RECIL 2017 criteria were used to assess response by central imaging review. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per 2019 ASTCT criteria. Adverse events (AEs) were graded by CTCAE v5.0.
Results: As of March 15, 2024, 51 pts with R/R DLBCL received AZD0486 at target doses of ≤0.8 mg (n=2), 2.4 mg (n=18 [2SUD, n=8]), 7.2 mg (n=19 [2SUD, n=15]), and 15 mg (n=12 [2SUD, n=12]). Median prior lines of therapy (pLOT) was 4 (range, 2-9) with 10 (20%) pts having received &gt;5 pLOT. Additionally, 31 (61%) pts previously received chimeric antigen receptor T-cell therapy (CAR-T), 14 (28%) pts previously received polatuzumab vedotin, 4 (8%) received prior CD20 TCE therapy, and 3 (6%) received other CD19-directed therapies; 20 (39%) pts were refractory to last line of therapy. Among the 40 efficacy-evaluable pts who received AZD0486 at doses ≥2.4 mg, the objective response rate (ORR) and CR rate were 43% and 33%, respectively. At a target dose of 7.2 mg, ORR was 47% (9/19) with a 42% (8/19) CR rate. Of 14 pts who previously progressed on CAR-T and received a target dose of 7.2 mg, the ORR and CR rate were 36% and 29%, respectively. Of 5 CAR-T-naive pts who received a target dose of 7.2 mg, ORR and CR rate were both 80%. With a median time on study of 7.5 months (range, 2.1-24.7) for pts who received a target dose of 7.2 mg, there was an estimated 12-mo duration of response rate of 75% and 12-mo overall survival rate of 77%. Grade 3/4 AEs observed in ≥10% of pts with DLBCL who received 2SUD were neutropenia (26%) and anemia (17%). No treatment-related deaths or AEs leading to discontinuation occurred. Among pts who received 2SUD (n=35), CRS events occurred in 12 (34%) pts (all grade 1), grade 1-2 ICANS occurred in 4 (11%) pts, and grade 3 ICANS occurred in 2 (5.7%) pts (0/2 at target dose); all CRS and ICANS events were fully reversible and without sequelae, limited to cycle 1, and did not lead to treatment discontinuation. Exposure-response analyses (n=46) demonstrated a relationship between higher Cavg of AZD0486 and higher probability of ORR and CR, and confirmed higher response rate at target dose of 7.2 mg and 15 mg vs doses ≤2.4 mg.
Conclusion: AZD0486 is active in pts with heavily pretreated DLBCL and responses appear to be target dose-dependent at least up to 15 mg. At target doses evaluated, AZD0486 was well tolerated, with 2SUD mitigating CRS and ICANS events. Dose escalation is ongoing.