Escalating Doses of AZD0486, a Novel CD19xCD3 T-Cell Engager, Result in High Complete Remissions with Rapid Clearance of Minimal Residual Disease in Patients with Relapsed/Refractory Follicular Lymphoma

Abstract

Introduction: AZD0486 is a novel, IgG4 fully human CD19xCD3 bispecific T-cell engager (TCE) with a low-affinity anti-CD3 moiety uniquely engineered to reduce cytokine release while maintaining potent antitumor cytotoxicity. AZD0486 is being evaluated in an ongoing first-in-human phase 1 study for patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) (NCT04594642). Here, we present efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) data from dose escalation of AZD0486 in pts with R/R follicular lymphoma (FL). Methods: Eligible pts had R/R CD19+ B-NHL that was R/R to ≥2 prior lines of therapy. Escalating doses of intravenous AZD0486 were administered in either a fixed target dose (day [D]1, D15 0.03-2.4 mg), single step-up dose (1SUD) schedule (D1 0.27-1 mg, D15 0.8-10 mg), or double SUD (2SUD) schedule (D1 0.27 mg, D8 1 mg, D15 2.4-15 mg) in cycle (C) 1. AZD0486 was then given every 2-4 weeks in 28-D Cs for C2-24. The primary objective was to assess safety, tolerability, and PK/PD and to determine the recommended phase 2 dose. Response was assessed by central imaging review per RECIL 2017 criteria. Minimal residual disease (MRD) was assessed by PhasED-Seq using Foresight CLARITY for Lymphoma test in plasma circulating tumor DNA. 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, 47 pts with R/R FL received AZD0486 at target doses of ≤0.8 mg (n=7), 2.4 mg (n=15 [2SUD, n=9]), 7.2 mg (n=20 [2SUD, n=16]), 10 mg (n=1), and 15 mg (n=4 [2SUD, n=4]). Overall, 18 (38.3%) pts had disease progression within 24 months of front-line chemoimmunotherapy (POD24). Median prior lines of therapy was 3 (range 2-12), 18 (38%) pts received prior lenalidomide-based therapy, 7 (15%) pts received prior chimeric antigen receptor T-cell therapy (CAR-T), and 4 (9%) received prior CD20 TCE therapy. The overall response rate (ORR) and complete response (CR) rate for evaluable pts receiving doses ≥2.4 mg (n=27) were96% and 85%, respectively; 6/7 (86%) pts with CD20-negative disease at baseline achieved CR, including 2/2 pts who had progressed after prior CD20 TCE therapy. Given the improved safety profile of AZD0486 with 2SUD, the 2SUD cohorts were expanded, and the CR rate was 88% (7/8) at a target dose of 7.2 mg and 75% (6/8) at a target dose of 2.4 mg. Exposure-response analysis also indicated improved ORR with higher exposure to AZD0486 (P=0.042, 7.2 mg vs 2.4 mg) and a trend of improved CR rate with higher exposure. Of the 19 pts with CR evaluable for MRD in the 2.4 mg and 7.2 mg cohorts, 89% (17/19) achieved undetectable MRD by 12 weeks. With median follow-up of 8.2 (range, 0.3-29.3) months (mo), for pts who received ≥0.8 mg (n=32), estimated 12-mo progression-free survival was 72% and 12-mo duration of response was 77%. Among pts treated with 2SUD (n=29), 13 (45%) had grade 1 CRS (7% at target dose) and 1 (3%) pt experienced grade 1 ICANS (0% at target dose). No grade ≥2 events of CRS or ICANS were reported in pts who received 2SUD. There was no meaningful difference in CRS or ICANS events observed at target dose of 7.2 mg vs 2.4 mg. The most common (≥5%) grade ≥3 TEAEs in pts who received 2SUD were lymphopenia (28%), neutropenia (10%), decreased white blood cell count (10%), and hyperglycemia (7%). In all pts with FL, the higher target dose of 7.2 mg was not associated with increased rates of treatment-related grade ≥3 AEs, serious AEs, all-grade AEs, or frequency/severity of cytopenias or infections. Moreover, no pt at any dose discontinued due to treatment-related AEs. Dose-limiting toxicities were mitigated with 2SUD; no maximum tolerated dose has been reached. Conclusion: AZD0486 offers high response rates in pts with R/R FL at target doses ≥2.4 mg. Responses were durable. 2SUD allows safe administration of the target dose up to at least 15 mg. The exposure-response analysis supports the target dose of 7.2 mg. Further studies of AZD0486 are planned as monotherapy and in combination regimens.

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